ANTI-WOLBACHIA PYRIDO[2,3-d]PYRIMIDINECOMPOUNDS

ABSTRACT

The present invention relates to compounds of Formulae I and II as defined herein, and salts and solvates thereof.The present invention also relates to pharmaceutical compositions comprising compounds of Formulae I and II, and to the use of compounds of Formulae I and II in the treatment or prevention of filarial worm infection, as well as other diseases or conditions in which filarial worm infection is implicated.

INTRODUCTION

This application relates to compounds of Formulae I and II as defined herein and salts or solvates thereof.

The compounds of Formula I and Formula II and their salts generally have anti-Wolbachia activity, and may be used to treat diseases or conditions mediated, at least in part, by a filarial worm infection.

The present application further provides pharmaceutical compositions comprising a compound of Formulae I or II and/or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.

The present application also provides methods of treating a disease or condition mediated, at least in part, by a filarial worm infection comprising administering to a subject in need a compound of Formula I or Formula II and/or a pharmaceutically acceptable salt or solvate thereof.

BACKGROUND OF THE INVENTION

Filarial nematodes are an important group of human pathogens infecting around 150 million people throughout the tropics with more than 1.5 billion at risk of infection. Filariasis accounts for some of the most debilitating global diseases that affect the ‘poorest of the poor’ resulting in a profound socio-economic impact on the most vulnerable in society.

Lymphatic filariasis is transmitted by infected mosquitoes. When an infected mosquito bites and takes a blood feed, worm larvae transfer from the mosquito onto the bite site where they enter into the body and move towards the lymphatic system - the system in the body which regulates the balance of fluids and fights infection. Here it will take the larvae 6 months to 1 year to develop into adult worms; the males will grow to approximately 2 to 4 cm long and the females to 4 to 10 cm long.

After mating, the female worms release thousands of larvae into the lymphatic system. These larvae migrate into the blood stream and transfer back into a mosquito when it bites. Once inside the mosquito, the larvae move to the mosquito stomach where they shed their sheaths before entering the mosquito body cavity and eventually into the flight muscles. After 10 to 14 days the juvenile worms are ready to migrate into the mouth-parts of the mosquito and the cycle is completed when the mosquito bites again.

Wuchereria bancrofti, Brugia malayi, and Brugia timori are causative agents of lymphatic filariasis, or elephantiasis, in humans. People suffering with lymphatic filariasis can develop hydrocele and lymphedema leading to elephantiasis. It is estimated that up to 120 million people in 83 countries worldwide are affected by lymphatic filariasis.

Onchocerciasis is transmitted by black flies which live and breed in rivers. Onchocerca volvulus is a causative agent of onchocerciasis, or river blindness, in humans. Manifestations of onchocerciasis result primarily from the intense inflammatory reaction to Wolbachia bacteria released into the skin and eyes upon the death of microfilaria. Onchocerciasis affects up to 37 million people worldwide and is most abundant in Africa.

Two of the major constraints of treatment of filarial diseases are (i) the absence of a macrofilaricidal drug (or for onchocerciasis, one which permanently sterilizes the worm) and (ii) the risk of worms developing drug-resistance. For example, currently available treatments for onchocerciasis include ivermectin, which kills worm larvae, but has little or no activity against adult Onchocerca volvulus parasites. Thus, infected patients must be retreated with ivermectin for several years until the adult worms die naturally. The most commonly used dose interval is 12 months; however, retreatment with ivermectin may be considered at intervals as short as 3 months. In addition, there are also potential signs of resistance to ivermectin within the parasite in a few areas (Osei-Atweneboana MY, et al. (2011) Phenotypic Evidence of Emerging Ivermectin Resistance in Onchocerca volvulus. PLoS Negl Trop Dis 5(3): e998).

In addition, there is a danger in treating patients co-infected with both (i) Wuchereria bancrofti, Brugia malayi, Brugia timori, and/or Onchocerca volvulus; and (ii) Loa loa with ivermectin. In such co-infected patients, ivermectin treatment can cause severe reactions, including encephalopathy, leading to coma or even death.

Thus, alternative, and more effective, treatments for filarial worm diseases and, in particular, onchocerciasis and lymphatic filariasis are needed.

Wolbachia is a genus of bacteria that infects arthropods, including insects and crusteans, and filarial worms such as Onchocerca volvulus, Wuchereria bancrofti, Brugia malayi, and Brugia timori. The bacteria reside in cytoplasmic vacuoles and are essential for development, reproduction and long-term survival of filarial worms. Accordingly, eliminating the bacteria with antibiotic drugs kills the worms and delivers a new and practical solution for eradicating the debilitating diseases mediated by these worms.

Antibiotics, such as doxycycline, minocycline, and rifampicin, have been demonstrated to be effective against Wolbachia. Taylor et al., (2005) Lancet 365(9477):2116-2121 and Townson S, et al., (2006) Filaria J.5:4. However, it has been reported that other classes of antibiotics, such as penicillins, aminoglycosides, and macrolides are ineffective at depleting Wolbachia from filariae (Hoerauf A, et al. (1999) Journal of Clinical Investigation 103(1):11-18 and Hoerauf A, et al. (2000) Trop Med Int Health 5(4):275-279).

Existing anti-Wolbachia drugs are non-optimal; they require a relatively long course of treatment (~4 weeks) and often exclude certain subjects, including pregnant women and children under the age of 9 (e.g., treatment with tetracyclines).

Thus, there exists a need for alternative and/or improved anti-Wolbachia treatments, such as those providing a shorter treatment regimen (e.g., 7 days or less) and/or usable in currently restricted populations (Taylor et al. Parasitology, 141(1):119-27).

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound of Formula I or II as defined herein, and/or a salt or solvate thereof.

In another aspect, the present invention provides a pharmaceutical composition which comprises a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.

In another aspect, the present invention provides a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.

In another aspect, the present invention provides a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a filarial worm infection.

In another aspect, the present invention provides a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a disease or condition mediated by a filarial worm infection.

In another aspect, the present invention provides a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a microbial infection.

In another aspect, the present invention provides the use of a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a filarial worm infection.

In another aspect, the present invention provides the use of a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition mediated by a filarial worm infection.

In another aspect, the present invention provides the use of a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a microbial infection.

In another aspect, the present invention provides a method of treating or preventing a filarial worm infection, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method of treating or preventing a disease mediated by a filarial worm infection, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method of treating a microbial infection, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

In another aspect, the present invention provides a combination comprising a compound of Formula I or II, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, with one or more additional therapeutic agents.

Preferred, suitable, and optional features of any one particular aspect of the present invention are also preferred, suitable, and optional features of any other aspect.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The compounds and intermediates described herein may be named according to either the IUPAC (International Union for Pure and Applied Chemistry) or CAS (Chemical Abstracts Service) nomenclature systems. It should be understood that unless expressly stated to the contrary, the terms “compounds of Formula I”, “compounds of Formula la”, “compounds of Formula II” and “compounds of Formula Ila”, and the more general term “compounds” refer to and include any and all compounds described by and/or with reference to Formula I, Ia, II and IIa respectively. It should also be understood that these terms encompasses all stereoisomers, i.e. cis and trans isomers, as well as optical isomers, i.e. R and S enantiomers, of such compounds and all salts thereof, in substantially pure form and/or any mixtures of the foregoing in any ratio. This understanding extends to pharmaceutical compositions and methods of treatment that employ or comprise one or more compounds of the Formula I, Ia, II and IIa, either by themselves or in combination with additional agents.

The various hydrocarbon-containing moieties provided herein may be described using a prefix designating the minimum and maximum number of carbon atoms in the moiety, e.g. “(C_(a)-_(b))” or “C_(a)-C_(b)” or “(a-b)C”. For example, (C_(a)-_(b))alkyl indicates an alkyl moiety having the integer “a” to the integer “b” number of carbon atoms, inclusive. Certain moieties may also be described according to the minimum and maximum number of members with or without specific reference to a particular atom or overall structure. For example, the terms “a to b membered ring” or “having between a to b members” refer to a moiety having the integer “a” to the integer “b” number of atoms, inclusive.

“About” when used herein in conjunction with a measurable value such as, for example, an amount or a period of time and the like, is meant to encompass reasonable variations of the value, for instance, to allow for experimental error in the measurement of said value.

As used herein by themselves or in conjunction with another term or terms, “alkyl” and “alkyl group” refer to a branched or unbranched saturated hydrocarbon chain. Unless specified otherwise, alkyl groups typically contain 1-10 carbon atoms, such as 1-6 carbon atoms or 1-4 carbon atoms or 1-3 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, tert-butyl, isobutyl, etc.

As used herein by themselves or in conjunction with another term or terms, “alkylene” and “alkylene group” refer to a branched or unbranched saturated hydrocarbon chain. Unless specified otherwise, alkylene groups typically contain 1-10 carbon atoms, such as 1-6 carbon atoms or 1-3 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, methylene (—CH₂—), the ethylene isomers (—CH(CH₃)— and —CH₂CH₂—), the propylene isomers (—CH(CH₃)CH₂—, —CH(CH₂CH═)—, —C(CH₃)═—, and —CH₂CH₂CH₂—), etc.

As used herein by themselves or in conjunction with another term or terms, “alkenyl” and “alkenyl group” refer to a branched or unbranched hydrocarbon chain containing at least one double bond. Unless specified otherwise, alkenyl groups typically contain 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, ethenyl, 3-buten-1-yl, 2-ethenylbutyl, and 3-hexen-1-yl.

As used herein by themselves or in conjunction with another term or terms, “alkynyl” and “alkynyl group” refer to a branched or unbranched hydrocarbon chain containing at least one triple bond. Unless specified otherwise, alkynyl groups typically contain 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, and 3-pentyn-1-yl.

As used herein by itself or in conjunction with another term or terms, “aromatic” refers to monocyclic and polycyclic ring systems containing 4n+2 pi electrons, where n is an integer. Aromatic should be understood as referring to and including ring systems that contain only carbon atoms (i.e. “aryl”) as well as ring systems that contain at least one heteroatom selected from N, O or S (i.e. “heteroaromatic” or “heteroaryl”). An aromatic ring system can be substituted or unsubstituted.

As used herein by itself or in conjunction with another term or terms, “non-aromatic” refers to a monocyclic or polycyclic ring system having at least one double bond that is not part of an extended conjugated pi system. As used herein, non-aromatic refers to and includes ring systems that contain only carbon atoms as well as ring systems that contain at least one heteroatom selected from N, O or S. A non-aromatic ring system can be substituted or unsubstituted.

As used herein by themselves or in conjunction with another term or terms, “aryl” and “aryl group” refer to phenyl and 7-15 membered bicyclic or tricyclic hydrocarbon ring systems, including bridged, spiro, and/or fused ring systems, in which at least one of the rings is aromatic. Aryl groups can be substituted or unsubstituted. Unless specified otherwise, an aryl group may contain 6 ring atoms (i.e., phenyl) or a ring system containing 9 to 15 atoms, such as 9 to 11 ring atoms, or 9 or 10 ring atoms. Representative examples include, but are not limited to, naphthyl, indanyl, 1,2,3,4-tetrahydronaphthalenyl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, and 6,7,8,9-tetrahydro-5H-benzocycloheptenyl. Suitably an aryl group is phenyl and naphthyl, suitably phenyl.

As used herein by themselves or in conjunction with another term or terms, “arylene” and “arylene group” refer to a phenylene (—C₆H₄—) or to 7 to 15 membered bicyclic or tricyclic hydrocarbon ring systems, including bridged, spiro, and/or fused ring systems, in which at least one of the rings is aromatic. Arylene groups can be substituted or unsubstituted. In some embodiments, an arylene group may contain 6 (i.e., phenylene) ring atoms or be a ring system containing 9 to 15 atoms; such as 9 to 11 ring atoms; or 9 or 10 ring atoms. Arylene groups can be substituted or unsubstituted.

As used herein by themselves or in conjunction with another term or terms, “alkylaryl” and “alkylaryl group” refer to an alkyl group in which a hydrogen atom is replaced by an aryl group, wherein alkyl group and aryl group are as previously defined, such as, for example, benzyl (C₆H₅CH₂—). Alkylaryl groups can be substituted or unsubstituted.

As used herein by themselves or in conjunction with another term or terms, “carbocyclic group” and “carbocycle” refer to monocyclic and polycyclic ring systems that contain only carbon atoms in the ring(s), i.e., hydrocarbon ring systems, without regard or reference to aromaticity or degree of unsaturation. Thus, carbocyclic group should be understood as referring to and including ring systems that are fully saturated (such as, for example, a cyclohexyl group), ring systems that are aromatic (such as, for example, a phenyl group), as well as ring systems having fully saturated, aromatic and/or unsaturated portions (such as, for example, cyclohexenyl, 2,3-dihydro-indenyl, and 1,2,3,4-tetrahydronaphthalenyl). The terms carbocyclic and carbocycle further include bridged, fused, and spirocyclic ring systems.

As used herein by themselves or in conjunction with another term or terms, “cycloalkyl” and “cycloalkyl group” refer to a non-aromatic carbocyclic ring system, that may be monocyclic, bicyclic, or tricyclic, saturated or unsaturated, and may be bridged, spiro, and/or fused. A cycloalkyl group may be substituted or unsubstituted. Unless specified otherwise, a cycloalkyl group typically contains from 3 to 12 ring atoms. In some instances a cycloalkyl group may contain 4 to 10 ring atoms (e.g., 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, etc.). Representative examples include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl, norbornenyl, bicyclo[2.2.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[3.3.2]decane. Suitably, cycloalkyl groups are selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

As used herein by themselves or in conjunction with another term or terms, “alkylcycloalkyl” and “alkylcycloalkyl group” refer to an alkyl group in which a hydrogen atom is replaced by a cycloalkyl group, wherein alkyl group and cycloalkyl group are as previously defined, such as, for example, cyclohexylmethyl (C₆H₁₁CH₂—). Alkylcycloalkyl groups can be substituted or unsubstituted.

As used herein by themselves or in conjunction with another term or terms, “haloalkyl” and “haloalkyl group” refer to alkyl groups in which one or more hydrogen atoms are replaced by halogen atoms. Haloalkyl includes both saturated alkyl groups as well as unsaturated alkenyl and alkynyl groups. Representative examples include, but are not limited to, —CF₃, —CHF₂, —CH₂F, —CF₂CF₃, —CHFCF₃, —CH₂CF₃, —CF₂CH₃, —CHFCH₃, —CF₂CF₂CF₃, —CF₂CH₂CH₃, —CF═CF₂, —CCl═CH₂, —CBr═CH₂, —Cl═CH₂, —C≡C—CF₃, —CHFCH₂CH₃ and —CHFCH₂CF₃. Haloalkyl groups can be substituted or unsubstituted. Suitably, a haloalkyl group is selected from CHF₂ and CF₃, suitably CF₃.

As used herein by themselves or in conjunction with another term or terms, “haloalkoxy” and “haloalkoxy group” refer to alkoxy groups (i.e. O-alkyl groups) in which one or more hydrogen atoms are replaced by halogen atoms. Haloalkoxy includes both saturated alkoxy groups as well as unsaturated alkenyl and alkynyl groups. Representative examples include, but are not limited to, —OCF₃, —OCHF₂, —OCH₂F, —OCF₂CF₃, —OCHFCF₃, —OCH₂CF₃, —OCF₂CH₃, —OCHFCH₃, —OCF₂CF₂CF₃, —OCF₂CH₂CH₃, —OCF═CF₂, —OCCl═CH₂, —OCBr═CH₂, —OCHFCH₂CH₃ and —OCHFCH₂CF₃. Haloalkoxy groups can be substituted or unsubstituted. Suitably, a haloalkyoxy group is selected from —OCHF₂ and —OCF₃, suitably —OCF₃.

As used herein by themselves or in conjunction with another term or terms, “halo” and “halogen” include fluorine, chlorine, bromine and iodine atoms and substituents.

As used herein by themselves or in conjunction with another term or terms, “heteroaryl” and “heteroaryl group” refer to (a) 5 and 6 membered monocyclic aromatic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and (b) 7 to15 membered bicyclic and tricyclic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and in which at least one of the rings is aromatic. In some instances, a heteroaryl group can contain two or more heteroatoms, which may be the same or different. Heteroaryl groups can be substituted or unsubstituted, and may be bridged, spiro, and/or fused. In some instances, a heteroaryl group may contain 5, 6, or 8 to 15 ring atoms. In other instances, a heteroaryl group may contain 5 to 10 ring atoms, such as 5, 6, 9, or 10 ring atoms. Representative examples include, but are not limited to, 2,3-dihydrobenzofuranyl, 1,2-dihydroquinolinyl, 3,4-dihydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, benzthiazinyl, chromanyl, furanyl, 2-furanyl, 3-furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, 2-, 3-, or 4-pyridinyl, pyrimidinyl, 2-, 4-, or 5-pyrimidinyl, pyrazolyl, pyrrolyl, 2- or 3-pyrrolyl, pyrazinyl, pyridazinyl, 3- or 4-pyridazinyl, 2-pyrazinyl, thienyl, 2-thienyl, 3-thienyl, tetrazolyl, thiazolyl, thiadiazolyl, triazinyl, triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidin-2-yl, pyridazin-4-yl, pyrazin-2-yl, naphthyridinyl, pteridinyl, phthalazinyl, purinyl, alloxazinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, cinnolinyl, furopyridinyl, indolinyl, indolizinyl, indolyl, or 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 3H-indolyl, quinazolinyl, quinoxalinyl, isoindolyl, isoquinolinyl, 10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienyl, 12-oxa-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienyl, 12-aza-tricyclo[7.2.1.0^(2,7)]dodeca-2(7),3,5-trienyl, 10-aza-tricyclo[6.3.2.0^(2,7)]trideca-2(7),3,5-trienyl, 2,3,4,5-tetrahydro-1H-benzo[d]azepinyl, 1,3,4,5-tetrahydro-benzo[d]azepin-2-onyl, 1,3,4,5-tetrahydro-benzo[b]azepin-2-onyl, 2,3,4,5-tetrahydro-benzo[c]azepin-1-onyl, 1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-onyl, 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl, 5,6,8,9-tetrahydro-7-oxa-benzocycloheptenyl, 2,3,4,5-tetrahydro-1H-benzo[b]azepinyl, 1,2,4,5-tetrahydro-benzo[e][1,3]diazepin-3-onyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, 3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-onyl, 6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptenyl, 5,5-dioxo-6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptenyl, and 2,3,4,5-tetrahydro-benzo[f][1,4]oxazepinyl. Suitably, a heteroaryl is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.

As used herein by themselves or in conjunction with another term or terms, “alkylheteroaryl” and “alkylheteroaryl group” refer to an alkyl group in which a hydrogen atom is replaced by a heteroaryl group, wherein alkyl group and heteroaryl group are as previously defined. Alkylheteroaryl groups can be substituted or unsubstituted. Where carbon numbers are provided, e.g. (C_(n)-_(m))alkylheteroaryl, the range refers to the whole group. Suitably, the consitutent alkyl group has 1-6 carbons, suitable 1-3 carbons.

As used herein by themselves or in conjunction with another term or terms, “heterocyclic group” and “heterocycle” refer to monocyclic and polycyclic ring systems that contain carbon atoms and at least one heteroatom selected from nitrogen, oxygen, sulfur or phosphorus in the ring(s), without regard or reference to aromaticity or degree of unsaturation. Thus, a heterocyclic group should be understood as referring to and including ring systems that are fully saturated (such as, for example, a piperidinyl group), ring systems that are aromatic (such as, for example, a pyrindinyl group), as well as ring systems having fully saturated, aromatic and/or unsaturated portions (such as, for example, 1,2,3,6-tetrahydropyridinyl and 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrizinyl). The terms heterocyclic and heterocycle further include bridged, fused, and spirocyclic ring systems.

As used herein by themselves or in conjunction with another term or terms, “heterocycloalkyl” and “heterocycloalkyl group” refer to 3 to15 membered monocyclic, bicyclic, and tricyclic non-aromatic ring systems, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen, sulfur or phosphorus. Heterocycloalkyl groups may be fully saturated or contain unsaturated portions and may be bridged, spiro, and/or fused ring systems. In some instances a heterocycloalkyl group may contain at least two or heteroatoms, which may be the same or different. Heterocycloalkyl groups can be substituted or unsubstituted. In some instances a heterocycloalkyl group may contain from 3 to 10 ring atoms or from 3 to 7 ring atoms or from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms. Representative examples include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl, homopiperazinyl, thiomorpholinyl-5-oxide, thiomorpholinyl-S,S-dioxide, pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-5-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-5-oxide, quinuclidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl, 3,8-diaza-bicyclo[3.2.1]octanyl, 2,5-diaza-bicyclo[2.2.1]heptanyl, 3,8-diaza-bicyclo[3.2.1]octanyl, 3,9-diaza-bicyclo[4.2.1]nonanyl, 2,6-diaza-bicyclo[3.2.2]nonanyl, [1,4]oxaphosphinanyl- 4-oxide, [1,4]azaphosphinanyl- 4-oxide, [1,2]oxaphospholanyl- 2-oxide, phosphinanyl-1-oxide, [1,3]azaphospholidinynl- 3-oxide, [1,3]oxaphospholanyl- 3-oxide, 7-oxabicyclo[2.2.1]heptanyl, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl, 6,8-dihydro-5H-imidazo[1,5-a]pyrazin-7-yl, 6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl, 5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]diazepin-7-yl and 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl. Suitably, a heterocyclylalkyl group as defined herein is a monocyclic, bicyclic or spiro heterocyclyl group comprising one, two or three heteroatoms selected from N, O or S.

As used herein by themselves or in conjunction with another term or terms, “heterocycloalkylene” and “heterocycloalkylene group” refer to 3 to 15 membered monocyclic, bicyclic, or tricyclic non-aromatic ring systems, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen, sulfur or phosphorus. Heterocycloalkylene groups may be fully saturated or contain unsaturated portions and may be bridged, spiro, and/or fused. Heterocycloalkylene groups can be substituted or unsubstituted. In some instances, a heterocycloalkylene group may contain from 3 to 10 ring atoms; such as from 3 to 7 ring atoms. In other instances a heterocycloalkylene group may contain from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms.

As used herein by themselves or in conjunction with another term or terms, “alkylheterocycloalkyl” and “alkylheterocycloalkyl group” refer to an alkyl group in which a hydrogen atom is replaced by a heterocycloalkyl group, wherein alkyl group and heterocycloalkyl group are as previously defined, such as, for example, pyrrolidinylmethyl (C₄H₈NCH₂—). Alkylheteroycloalkyl groups can be substituted or unsubstituted. Where carbon numbers are provided, e.g. (C_(n)-_(m))alkylheterocycloalkyl, the range refers to the whole group. Suitably, the consitutent alkyl group has 1-6 carbons, suitable 1-3 carbons.

As used herein by itself or in conjunction with another term or terms, “pharmaceutically acceptable” refers to materials that are generally chemically and/or physically compatible with other ingredients (such as, for example, with reference to a formulation), and/or is generally physiologically compatible with the recipient (such as, for example, a subject) thereof.

As used herein by itself or in conjunction with another term or terms, “pharmaceutical composition” refers to a composition that can be used to treat a disease, condition, or disorder in a subject, including a human.

As used herein by itself or in conjunction with another term or terms, “pseudohalogen” refers to —OCN, —SCN, —CF₃, and —CN.

As used herein by themselves or in conjunction with another term or terms, “stable” and “chemically stable” refer to a compound that is sufficiently robust to be isolated from a reaction mixture with a useful degree of purity. The present application is directed solely to the preparation of stable compounds. When lists of alternative substituents include members which, owing to valency requirements, chemical stability, or other reasons, cannot be used to substitute a particular group, the list is intended to be read in context to include those members of the list that are suitable for substituting the particular group. For example, when considering the degree of optional substitution of a particular moiety, it should be understood that the number of substituents does not exceed the valency appropriate for that moiety. For example, if R¹ is a methyl group (—CH₃), it can be optionally substituted by 1 to 3 R⁵.

As used herein by themselves or in conjunction with another term or terms, “subject(s)” and “patient(s)”, suitably refer to mammals, in particular humans.

As used herein by itself or in conjunction with another term or terms, “substituted” indicates that a hydrogen atom on a molecule has been replaced with a different atom or group of atoms and the atom or group of atoms replacing the hydrogen atom is a “substituent.” It should be understood that the terms “substituent”, “substituents”, “moiety”, “moieties”, “group”, or “groups” refer to substituent(s).

As used herein by themselves or in conjunction with another term or terms, “therapeutic” and “therapeutically effective amount” refer to an amount a compound, composition or medicament that (a) inhibits or causes an improvement in a particular disease, condition or disorder; (b) attenuates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder; (c) or delays the onset of one or more symptoms of a particular disease, condition or disorder described herein. It should be understood that the terms “therapeutic” and “therapeutically effective” encompass any one of the aforementioned effects (a)-(c), either alone or in combination with any of the others (a)-(c). It should be understood that in, for example, a human or other mammal, a therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or a therapeutically effective amount may be the amount required by the guidelines of the United States Food and Drug Administration (FDA) or equivalent foreign regulatory body, for the particular disease and subject being treated. It should be appreciated that determination of proper dosage forms, dosage amounts, and routes of administration is within the level of ordinary skill in the pharmaceutical and medical arts.

As used herein whether by themselves or in conjunction with another term or terms, “treating”, “treated” and “treatment”, refer to and include prophylactic, ameliorative, palliative, and curative uses and results. In some embodiments, the terms “treating”, “treated”, and “treatment” refer to curative uses and results as well as uses and results that diminish or reduce the severity of a particular condition, characteristic, symptom, disorder, or disease described herein. For example, treatment can include diminishment of several symptoms of a condition or disorder or complete eradication of said condition or disorder. It should be understood that the term “prophylactic” as used herein is not absolute but rather refers to uses and results where the administration of a compound or composition diminishes the likelihood or seriousness of a condition, symptom, or disease state, and/or delays the onset of a condition, symptom, or disease state for a period of time.

As used herein, a “therapeutically active agent”, whether used alone or in conjunction with another term or terms, refers to any compound, i.e. a drug, that has been found to be useful in the treatment of a disease, disorder or condition and is not described by Formula I. It should be understood that a therapeutically active agent may not be approved by the FDA or an equivalent foreign regulatory body.

A “therapeutically effective amount” means the amount of a compound that, when administered to a subject or patient for treating a disease, is sufficient to effect such treatment for the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject or patient to be treated.

Compounds

In one aspect, the present invention relates to compounds of Formula I:

or a salt or solvate thereof, wherein,

-   A represents a fused aromatic ring selected from,

-   

-   

-   X¹, X² and X³ are independently selected from N and CH;

-   Q is a group selected from an C₃₋₁₁cycloalkyl optionally substituted     by one or more R^(b), 3-15 membered heterocycloalkyl optionally     substituted by one or more R^(b), C₆₋₁₁ aryl group optionally     substituted with by one or more R^(b), 5-15 membered heteroaryl     optionally substituted by one or more R^(b);

-   R⁶ is selected from hydrogen and C₁₋₆ alkyl;

-   R⁷ and R⁷′ are independently selected from hydrogen, C₃₋₆     cycloalkyl, C₁₋₆ alkyl, where said C₃₋₆ cycloalkyl and C₁₋₆ alkyl     are optionally substituted by one or more R^(a); or

-   R⁷ and R⁷′, together with the carbon to which they are attached form     a 3-7 membered cycloalkyl ring, optionally substituted with one or     more R^(a), or R⁷ and R⁷′, together with the carbon to which they     are attached form a carbonyl group; or

-   R⁶ and R⁷, together with the atoms to which they are attached form a     3-7 membered heterocyclic ring, optionally substituted with one or     more R^(a);

-   n is a number selected from 1, 2 and 3;

-   R² is selected from —CN, —C(═O)R^(d), —C(═O)OR^(d),     —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d),     -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)R^(d),     —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d),     —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d), —OC(═O)R^(d),     —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)R^(d), —S(═O)₂R^(d),     —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d),     —OS(═O)₂NR^(c)R^(d), —S(═O)₂NR^(c)R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl     optionally substituted by one or more R^(e), C₂₋₆alkenyl optionally     substituted by one or more R^(e), C₂₋₆alkynyl optionally substituted     by one or more R^(e), C₆₋₁₁aryl optionally substituted by one or     more R^(e), (C₇₋₁₆)alkylaryl optionally substituted by one or more     R^(e), C₃₋₁₁cycloalkyl optionally substituted by one or more R^(e),     (C₄₋ ₁₇)cycloalkylalkyl optionally substituted by one or more R^(e),     3-15 membered heterocycloalkyl optionally substituted by one or more     R^(e), 4-21 membered alkylheterocycloalkyl optionally substituted by     one or more R^(e), 5-15 membered heteroaryl optionally substituted     by one or more R^(e), and 6-21 membered alkylheteroaryl optionally     substituted by one or more R^(e);

-   each R^(a) is independently selected from hydroxyl, halogen, CN,     C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7     membered heterocycloalkyl, wherein said C₃₋₆ cycloalkyl and 3-7     membered heterocycloalkyl are optionally substituted with one or     more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl,     C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋ ₆ alkyl;

-   each R^(b) and R^(e) is independently selected from hydroxyl, =O,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, O-C₁₋₆     alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, —C(═O)R^(d),     —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d),     —NR^(c)C(═O)R^(d), —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d),     —NR^(c)S(═O)₂R^(d), —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d),     —OC(═O)R^(d), —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)₂R^(d),     —S(═O)R^(d), —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d),     —S(═O)NR^(c)R^(d), —OS(═O)₂NR^(c)R^(d), and —S(═O)₂NR^(c)R^(d),     where said C₃₋₆ cycloalkyl, C₁₋₆ alkyl, and 3-7 membered     heterocycloalkyl are optionally substituted with one or more groups     selected from hydroxyl, halogen, =O, CN, C₁₋₆ haloalkyl, C₁₋₆     haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl;

-   each R^(c) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆     alkyl;

-   each R^(d) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, 3-7 membered heterocycloalkyl, C₃₋₆     cycloalkyl, C₁₋₆ alkyl, O-C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said     C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆     cycloalkyl are optionally substituted with one or more groups     selected from hydroxyl, halogen, CN, amino, C₁₋₆ haloalkyl, C₃₋₆     cycloalkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl, C₁₋₆ alkyl     and O-C₁₋₆ alkyl; or

-   R^(c) and R^(d), when attached to the same atom, together with the     atom to which they are attached form a 3-7 membered ring, optionally     containing one or more for heteroatoms selected from O, NH and S,     and wherein said ring is optionally substituted with one or more     R^(a);

-   R³, R⁴ and R⁵ are independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, phenyl and     cyclopropyl, wherein said C₁₋₆ alkyl, phenyl and cyclopropyl are     optionally substituted by one or more R^(a);

-   with the provisos that:     -   (i) when X¹ is N, X² and X³ cannot both be CH;     -   (ii) when Q is phenyl, R^(b) is not such that Q is a         3,4-di-O-C₁₋₆ alkyl phenyl, a 3,5-di-O-C₁₋₆ alkyl phenyl or a         3,4,5-tri-O-C₁₋₆ alkyl phenyl; and     -   (iii) the compound of Formula (l) is not         -   •N-(4-fluorobenzyl)-2-(piperidinyl-1-yl)pyrido[2,3-d]pyrimidin-4-amine,         -   •N-(4-fluorobenzyl)-2-(piperidinyl-1-yl)pyrido[3,2-d]pyrimidin-4-amine,         -   •N-(4-fluorobenzyl)-2-(piperidinyl-1-yl)thieno[3,2-d]pyrimidin-4-amine.

The invention will now be further described by way of the following numbered paragraphs:

1. A compound of Formula I, or a salt or solvate thereof, wherein,

-   A represents a fused aromatic ring selected from,

-   

-   

-   X¹, X² and X³ are independently selected from N and CH;

-   Q is a group selected from an C₃₋₁₁cycloalkyl optionally substituted     by 1-21 R^(b), 3-15 membered heterocycloalkyl optionally substituted     by 1-28 R^(b), C₆₋₁₁ aryl group optionally substituted with by 1-11     R^(b), 5-15 membered heteroaryl optionally substituted by 1-15     R^(b);

-   R⁶ is selected from hydrogen and C₁₋₆ alkyl;

-   R⁷ and R⁷′ are independently selected from hydrogen, C₃₋₆     cycloalkyl, C₁₋₆ alkyl, where said C₃₋₆ cycloalkyl and C₁₋₆ alkyl     are optionally substituted by one or more R^(a); or

-   R⁷ and R⁷′, together with the carbon to which they are attached form     a 3-7 membered cycloalkyl ring, optionally substituted with one or     more R^(a), or R⁷ and R⁷′, together with the carbon to which they     are attached form a carbonyl group; or

-   R⁶ and R⁷, together with the atoms to which they are attached form a     3-7 membered heterocyclic ring, optionally substituted with one or     more R^(a);

-   n is a number selected from 1, 2 and 3;

-   R² is selected from —CN, —C(═O)R^(d), —C(═O)OR^(d),     —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d),     -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)R^(d),     —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d),     —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d), —OC(═O)R^(d),     —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)R^(d), —S(═O)₂R^(d),     —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d),     —OS(═O)₂NR^(c)R^(d), —S(═O)₂NR^(c)R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl     optionally substituted by 1-13 R^(e), C₂₋ ₆alkenyl optionally     substituted by 1-11 R^(e), C₂₋₆alkynyl optionally substituted by 1-9     R^(e), C₆₋₁₁aryl optionally substituted by 1-11 R^(e),     (C₇₋₁₆)alkylaryl optionally substituted by 1-9 R^(e), C₃₋     ₁₁cycloalkyl optionally substituted by 1-21 R^(e),     (C₄₋₁₇)cycloalkylalkyl optionally substituted by 1-32 R^(e), 3-15     membered heterocycloalkyl optionally substituted by 1-28 R^(e), 4-21     membered alkylheterocycloalkyl optionally substituted by 1-40 R^(e),     5-15 membered heteroaryl optionally substituted by 1-15 R^(e), and     6-21 membered heteroarylalkyl optionally substituted by 1-27 R^(e);

-   each R^(a) is independently selected from hydroxyl, halogen, CN,     C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7     membered heterocycloalkyl, wherein said C₃₋₆ cycloalkyl and 3-7     membered heterocycloalkyl are optionally substituted with one or     more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl,     C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋ ₆ alkyl;

-   each R^(b) and R^(e) is independently selected from hydroxyl, =O,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, O-C₁₋₆     alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, —C(═O)R^(d),     —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d),     —NR^(c)C(═O)R^(d), —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d),     —NR^(c)S(═O)₂R^(d), —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d),     —OC(═O)R^(d), —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)₂R^(d),     —S(═O)R^(d), —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d),     —S(═O)NR^(c)R^(d), —OS(═O)₂NR^(c)R^(d), and —S(═O)₂NR^(c)R^(d),     where said C₃₋₆ cycloalkyl, C₁₋₆ alkyl, and 3-7 membered     heterocycloalkyl are optionally substituted with one or more groups     selected from hydroxyl, halogen, =O, CN, C₁₋₆ haloalkyl, C₁₋₆     haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl;

-   each R^(c) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆     alkyl;

-   each R^(d) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, 3-7 membered heterocycloalkyl, C₃₋₆     cycloalkyl, C₁₋₆ alkyl, O-C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said     C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆     cycloalkyl are optionally substituted with one or more groups     selected from hydroxyl, halogen, CN, amino, C₁₋₆ haloalkyl, C₃₋₆     cycloalkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl, C₁₋₆ alkyl     and O-C₁₋₆ alkyl; or

-   R^(c) and R^(d), when attached to the same atom, together with the     atom to which they are attached form a 3-7 membered ring, optionally     containing one or more for heteroatoms selected from O, NH and S,     and wherein said ring is optionally substituted with one or more     R^(a);

-   R³, R⁴ and R⁵ are independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, phenyl and     cyclopropyl, wherein said C₁₋₆ alkyl, phenyl and cyclopropyl are     optionally substituted by one or more R^(a);

-   with the provisos that:     -   (i) when X¹ is N, X² and X³ cannot both be CH;     -   (ii) when Q is phenyl, R^(b) is not such that Q is a         3,4-di-O-C₁₋₆ alkyl phenyl, a 3,5-di-O-C₁₋₆ alkyl phenyl or a         3,4,5-tri-O-C₁₋₆ alkyl phenyl; and     -   (iii) the compound of Formula (l) is not         -   •N-(4-fluorobenzyl)-2-(piperidinyl-1-yl)pyrido[2,3-d]pyrimidin-4-amine,         -   •N-(4-fluorobenzyl)-2-(piperidinyl-1-yl)pyrido[3,2-d]pyrimidin-4-amine,         -   •N-(4-fluorobenzyl)-2-(piperidinyl-1-yl)thieno[3,2-d]pyrimidin-4-amine.

2. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein A is

3. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein X¹ is N.

4. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein one of X² and X³ is N and the other is CH.

5. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein X² is CH and X³ is N.

6. A compound according to any one of paragraphs 1 to 3, or a salt or solvate thereof, wherein X¹ is N and A is selected from

7. A compound according to any one of paragraphs 1 to 3, or a salt or solvate thereof, wherein A is

8. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein Q is a group selected from a 3-15 membered heterocycloalkyl optionally substituted by one or more R^(b), C₆₋₁₁ aryl group optionally substituted with by one or more R^(b), and a 5-15 membered heteroaryl optionally substituted by one or more R^(b).

9. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein Q is a group selected from a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(b), C₆₋₁₁ aryl group optionally substituted with by 1-11 R^(b), and a 5-15 membered heteroaryl optionally substituted by 1-15 R^(b).

10. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein Q is a group selected from a C₆₋₁₁ aryl group optionally substituted with by 1-11 R^(b) and a 5-15 membered heteroaryl optionally substituted by 1-15 R^(b).

11. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein Q is a group selected from a C₆ aryl group optionally substituted with by one or more R^(b) and a 5-6 membered heteroaryl optionally substituted by one or more R^(b).

12. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein Q is selected from a phenyl or pyridyl group optionally substituted with 1-5 R^(b).

13. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein Q is a group of Formula III (wherein the dotted line indicates the point of attachment):

wherein

-   X⁴ is selected from CH and N; -   m is selected from 0, 1 and 2; and -   R^(b) is as previously defined.

14. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein Q is a group of Formula Illa:

wherein

-   X⁴ is selected from CH and N, suitably N; and -   R^(b) is as previously defined.

15. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein each R^(b) is independently selected from hydroxyl, =O, halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆ alkyl, O-C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, —NR^(c)R^(d), —NR^(c)C(═O)R^(d), —OR^(d), —SR^(d), —S(═O)₂R^(d), —S(═O)R^(d), —S(═O)NR^(c)R^(d), and —S(═O)₂NR^(c)R^(d), where said C₃₋₆ cycloalkyl, C₁₋₆ alkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

16. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein each R^(b) is independently selected from hydroxyl, =O, halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, O-C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, —NR^(c)R^(d), and —S(═O)₂R^(d), where said C₃₋₆ cycloalkyl, C₁₋₆ alkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋ ₆ alkyl.

17. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein each R^(b) is independently selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

18. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein each R^(b) is independently selected from fluoro, chloro, and CF₃.

19. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein Q is selected from:

20. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R⁶ is selected from hydrogen, methyl and ethyl.

21. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R⁶ is selected from hydrogen and methyl.

22. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R⁷ and R⁷′ are independently selected from hydrogen, methyl and cyclopropyl.

23. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R⁷ and R⁷′ are independently selected from hydrogen and methyl.

24. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R⁷′ is hydrogen.

25. A compound according to any one of paragraphs 1 to 21, or a salt or solvate thereof, wherein R⁷ and R⁷′, together with the atom to which they are attached form a C₃₋₆ cycloalkyl ring, optionally substituted by one or more R^(a).

26. A compound according to any one of paragraphs 1 to 21, or a salt or solvate thereof, wherein R⁷ and R⁷′, together with the atom to which they are attached form a cyclopropyl ring, optionally substituted by one or more R^(a).

27. A compound according to any one of paragraphs 1 to 24 wherein R⁶ and R^(7′) are both hydrogen.

28. A compound according to any one of paragraphs 1 to 24 wherein R⁶, R⁷ and R^(7′) are each hydrogen.

29. A compound according to any one of paragraphs 1 to 19, or a salt or solvate thereof, wherein R⁶ and R⁷ together with the atoms to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl ring.

30. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein n is 1 or 2.

31. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein n is 1.

32. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R² is selected from —CN, —C(═O)R^(d), —C(═O)OR^(d), —C(═O)NR^(C)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d), -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)R^(d), —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d), —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d) —OC(═O)R^(d), —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)R^(d), —S(═O)₂R^(d), —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d), —OS(═O)₂NR^(c)R^(d), —S(═O)₂NR^(c)R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl optionally substituted by 1-13 R^(e), C₂₋₆alkenyl optionally substituted by 1-11 R^(e), C₂₋₆alkynyl optionally substituted by 1-9 R^(e), C₆₋₁₁aryl optionally substituted by 1-11 R^(e), (C₇₋₁₆)alkylaryl optionally substituted by 1-9 R^(e), C₃₋₁₁cycloalkyl optionally substituted by 1-21 R^(e), (C₄₋ ₁₇)cycloalkylalkyl optionally substituted by 1-32 R^(e), 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e), 4-21 membered alkylheterocycloalkyl optionally substituted by 1-40 R^(e), 5-15 membered heteroaryl optionally substituted by 1-15 R^(e), and 6-21 membered alkylheteroaryl optionally substituted by 1-27 R^(e);

33. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R² is selected from —CN, —C(═O)R^(d), —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d), -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)R^(d), —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d), —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d) —OC(═O)R^(d), —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)R^(d), —S(═O)₂R^(d), —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d), —OS(═O)₂NR^(c)R^(d), —S(═O)₂NR^(c)R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl optionally substituted by 1-13 R^(e), C₂₋₆alkenyl optionally substituted by 1-11 R^(e), C₂₋₆alkynyl optionally substituted by 1-9 R^(e), C₆₋₁₁aryl optionally substituted by 1-11 R^(e), (C₇₋₁₆)alkylaryl optionally substituted by 1-9 R^(e), C₃₋₁₁cycloalkyl optionally substituted by 1-21 R^(e), (C₄₋ ₁₇)cycloalkylalkyl optionally substituted by 1-32 R^(e), 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e), 4-21 membered alkylheterocycloalkyl optionally substituted by 1-40 R^(e), 5-15 membered heteroaryl optionally substituted by 1-15 R^(e), and 6-21 membered alkylheteroaryl optionally substituted by 1-27 R^(e);

34. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R² is selected from —CN, —C(═O)R^(d), —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —NR^(c)R^(d), -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)R^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d), —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d) —OC(═O)R^(d), —S(═O)R^(d), —S(═O)₂R^(d), —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d), —OS(═O)₂NR^(c)R^(d), —S(═O)₂NR^(c)R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl optionally substituted by 1-13 R^(e), C₆₋₁₁aryl optionally substituted by 1-11 R^(e), C₃₋₁₁cycloalkyl optionally substituted by 1-21 R^(e), 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e), and 5-15 membered heteroaryl optionally substituted by 1-15 R^(e).

35. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R² is selected from —CN, —C(═O)R^(d), C(═O)NR^(c)R^(d), —NR^(c)R^(d), -NR^(c)(C₁₋ ₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)NR^(c)R^(d), —OR^(d), —SR^(d), —S(═O)₂R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl optionally substituted by 1-13 R^(e), C₆₋₁₁aryl optionally substituted by 1-11 R^(e), C₃₋₁₁cycloalkyl optionally substituted by 1-21 R^(e), 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e), and 5-15 membered heteroaryl optionally substituted by 1-15 R^(e).

36. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R² is selected from NR^(c)R^(d), -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)NR^(c)R^(d), —OR^(d), —SR^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl optionally substituted by 1-13 R^(e), C₆₋₁₁aryl optionally substituted by 1-11 R^(e), C₃₋₁₁cycloalkyl optionally substituted by 1-21 R^(e), 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e), and 5-15 membered heteroaryl optionally substituted by 1-15 R^(e).

37. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R² is selected from NR^(c)R^(d), -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), C₁₋₁₀alkyl optionally substituted by 1-13 R^(e), C₆₋₁₁aryl optionally substituted by 1-11 R^(e), C₃₋₁₁cycloalkyl optionally substituted by 1-21 R^(e), 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e), and 5-15 membered heteroaryl optionally substituted by 1-15 R^(e).

38. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R² is selected from NR^(c)R^(d), -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), C₁₋₁₀alkyl optionally substituted by 1-13 R^(e), and 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e). Suitably, R^(c) is C₁₋₆alkyl, and R^(d) is independently selected from C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

39. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R² is selected from NR^(c)R^(d) and a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e). Suitably, R^(c) is C₁₋₆ alkyl, and R^(d) is independently selected from C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

40. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R² is selected from NR^(c)R^(d) and a 5-10 membered heterocycloalkyl optionally substituted by one or more R^(e). Suitably, R^(c) is C₁₋₆ alkyl, and R^(d) is independently selected from C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

41. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R² is selected from NR^(c)R^(d) and a 5-7 membered heterocycloalkyl optionally substituted by one or more R^(e). Suitably, R^(c) is C₁₋₆ alkyl, and R^(d) is independently selected from C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

42. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R² is selected from NR^(c)R^(d), azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, wherein said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl are optionally substituted by one or more R^(e). Suitably, R^(c) is C₁₋₆ alkyl, and R^(d) is independently selected from C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

43. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R² is selected from NR^(c)R^(d); and

each of which may optionally be substituted with one or more R^(e). Suitably, R^(c) is C₁₋₆ alkyl, and R^(d) is independently selected from C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

44. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R² is selected from

each of which may optionally be substituted with one or more R^(e).

45. A compound according to any one of paragraphs 1 to 43, or a salt or solvate thereof, wherein R² is selected from

46. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R^(e) is independently selected from hydroxyl, =O, halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, O-C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, —NR^(c)R^(d), where said C₃₋₆ cycloalkyl, C₁₋₆ alkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

47. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R^(e) is independently selected from hydroxyl, =O, halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

48. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R^(e) is independently selected from halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

49. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R^(e) is independently selected from halogen, CN, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₁₋₃ alkyl and O-C₁₋₃ alkyl.

50. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R^(e) is independently selected from fluoro, chloro, CN, CF₃, OCF₃ and C₁₋₃ alkyl.

51. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein each R^(e) is independently selected from fluoro, chloro, CN, CF₃, OCF₃, and methyl.

52. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein each R^(c) is independently selected from hydrogen, hydroxyl, C₁₋₆ haloalkyl, C₃₋ ₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl;

53. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein each R^(c) is independently selected from hydrogen and C₁₋₆alkyl, suitably C₁₋₆ alkyl.

54. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein each R^(c) is independently selected from hydrogen and C₁₋₃ alkyl, suitably C₁₋₃ alkyl.

55. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein each R^(d) is independently selected from hydrogen, 3-7 membered heterocycloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

56. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein each R^(d) is independently selected from 3-7 membered heterocycloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆alkyl and O-C₁₋₆ alkyl.

57. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein each R^(d) is independently selected from C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

58. A compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R^(c) and R^(d) are independently selected from C₁₋₆ alkyl.

59. A compound according to any one of the preceding paragraphs wherein R³, R⁴ and R⁵ are independently selected from hydrogen, halogen and C₁₋₆ alkyl.

60. A compound according to any one of the preceding paragraphs wherein R³ is H.

61. A compound according to any one of the preceding paragraphs wherein R⁴ is H.

62. A compound according to any one of the preceding paragraphs wherein R⁵ is H.

63. A compound according to any one of the preceding paragraphs wherein R⁴ and R⁵ are H.

64. A compound according to any one of the preceding paragraphs wherein R³, R⁴ and R⁵ are H.

65. A compound according to paragraph 1, or a salt or solvate thereof, which is a sub-Formula Ia:

wherein,

-   R⁶ is selected from hydrogen and C₁₋₆ alkyl; -   R⁷ is selected from hydrogen, =O, C₃₋₆ cycloalkyl, C₁₋₆ alkyl, where     said C₃₋₆ cycloalkyl, C₁₋₆ alkyl are optionally substituted by one     or more R^(a); or -   R⁶ and R⁷, together with the atoms to which they are attached form a     3-7 membered heterocyclic ring, optionally substituted with one or     more R^(a); -   R² is selected from —CN, —C(═O)R^(d), —C(═O)OR^(d),     —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d),     -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)R^(d),     —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d),     —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d) —OC(═O)R^(d),     —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)R^(d), —S(═O)₂R^(d),     —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d),     —OS(═O)₂NR^(c)R^(d), —S(═O)₂NR^(c)R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl     optionally substituted by 1-13 R^(e), C₂₋ ₆alkenyl optionally     substituted by 1-11 R^(e), C₂₋₆alkynyl optionally substituted by 1-9     R^(e), C₆₋₁₁aryl optionally substituted by 1-11 R^(e),     (C₇₋₁₆)alkylaryl optionally substituted by 1-9 R^(e), C₃₋     ₁₁cycloalkyl optionally substituted by 1-21 R^(e),     (C₄₋₁₇)cycloalkylalkyl optionally substituted by 1-32 R^(e), 3-15     membered heterocycloalkyl optionally substituted by 1-28 R^(e), 4-21     membered alkylheterocycloalkyl optionally substituted by 1-40 R^(e),     5-15 membered heteroaryl optionally substituted by 1-15 R^(e), and     6-21 membered alkylheteroaryl optionally substituted by 1-27 R^(e); -   each R^(a) is independently selected from hydroxyl, halogen, CN,     C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7     membered heterocycloalkyl, wherein said C₃₋₆ cycloalkyl, 3-7     membered heterocycloalkyl are optionally substituted with one or     more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl,     C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl; -   each R^(b) and R^(e) is independently selected from hydroxyl, =O,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆     alkyl, O-C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl,     —C(═O)R^(d), —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d),     —NR^(c)R^(d), —NR^(c)C(═O)R^(d), —NR^(c)C(═O)OR^(d),     —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d),     —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d), —OC(═O)R^(d),     —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)₂R^(d), —S(═O)R^(d),     —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d),     —OS(═O)₂NR^(c)R^(d), and —S(═O)₂NR^(c)R^(d), where said C₃₋₆     cycloalkyl, C₁₋₆ alkyl, and 3-7 membered heterocycloalkyl are     optionally substituted with one or more groups selected from     hydroxyl, halogen, =O, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₆     cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl; -   each R^(c) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆     alkyl; -   each R^(d) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, 3-7 membered heterocycloalkyl, C₃₋₆     cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl, C₆₋₁₁ aryl, wherein said     C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆     cycloalkyl are optionally substituted with one or more groups     selected from hydroxyl, =O, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆     cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆alkyl; or -   R^(c) and R^(d), when attached to the same atom, together with the     atom to which they are attached form a 3-7 membered ring, optionally     substituted with one or more R^(a); and -   R⁴ and R⁵ are independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, and C₁₋₆ alkyl;     optionally substituted by one or more R^(a).

66. A compound according to paragraph 65, or a salt or solvate thereof, wherein R⁴ and R⁵ are hydrogen.

67. A compound according to any one of paragraphs 65 and 66, or a salt or solvate thereof, wherein each R^(b) is independently selected from fluoro, chloro, and CF₃.

68. A compound according to any one of paragraphs 65 to 67 wherein R⁶ and R⁷ are both hydrogen.

69. A compound according to any one of paragraphs 65 to 68, or a salt or solvate thereof, wherein R² is selected from —CN, —C(═O)R^(d), C(═O)NR^(c)R^(d), —NR^(c)R^(d), -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)NR^(c)R^(d), —OR^(d), —SR^(d), —S(═O)₂R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl optionally substituted by 1-13 R^(e), C₆₋₁₁aryl optionally substituted by 1-11 R^(e), C₃₋₁₁cycloalkyl optionally substituted by 1-21 R^(e), 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e), and 5-15 membered heteroaryl optionally substituted by 1-15 R^(e). Suitably, R^(c) is C₁₋₆ alkyl, and R^(d) is independently selected from C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

70. A compound according to any one of paragraphs 65 to 69, or a salt or solvate thereof, wherein R² is selected from NR^(c)R^(d), -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), C₁₋₁₀alkyl optionally substituted by 1-13 R^(e), and 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e). Suitably, R^(c) is C₁₋₆ alkyl, and R^(d) is independently selected from C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

71. A compound according to any one of paragraphs 65 to 70, or a salt or solvate thereof, wherein R² is selected from NR^(c)R^(d); and

each of which may optionally be substituted with one or more R^(e). Suitably, R^(c) is C₁₋₆ alkyl, and R^(d) is independently selected from C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

72. A compound according to any one of paragraphs 65 to 71, or a salt or solvate thereof, wherein R² is selected from

each of which may optionally be substituted with one or more R^(e).

73. A compound according to any one of paragraphs 65 to 72, or a salt or solvate thereof, wherein R² is selected from

74. A compound according to any one of paragraphs 65 to 72, or a salt or solvate thereof, wherein each R^(e) is independently selected from fluoro, chloro, CN, CF₃, OCF₃, and methyl.

75. A compound according to any one of paragraphs 65 to 74, or a salt or solvate thereof, wherein R^(c) and R^(d) are independently selected from C₁₋₆ alkyl.

76. A compound, or a salt or solvate thereof, selected from:

-   2-chloro-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   N²-isopropyl-N⁴-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidine-2,4-diamine     methanesulfonate -   2-chloro-N-(2-fluorobenzyl)thieno[3,2-d]pyrimidin-4-amine -   N⁴-(2-fluorobenzyl)-N²-isopropylthieno[3,2-d]pyrimidine-2,4-diamine -   N⁴-benzyl-N²-isopropylthieno[3,2-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-(4-methoxybenzyl)thieno[3,2-d]pyrimidine-2,4-diamine -   N⁴-(3-fluorobenzyl)-N²-isopropylthieno[3,2-d]pyrimidine-2,4-diamine -   N⁴-(4-fluorobenzyl)-N²-isopropylthieno[3,2-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-(3-methoxybenzyl)thieno[3,2-d]pyrimidine-2,4-diamine -   N⁴-(2-chlorobenzyl)-N²-isopropylthieno[3,2-d]pyrimidine-2,4-diamine -   N⁴-(3-chlorobenzyl)-N²-isopropylthieno[3,2-d]pyrimidine-2,4-diamine -   N⁴-(4-chlorobenzyl)-N²-isopropylthieno[3,2-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-(2-methoxybenzyl)thieno[3,2-d]pyrimidine-2,4-diamine -   2-chloro-N-(2-chlorobenzyl)thieno[3,2-d]pyrimidin-4-amine -   N-(2-fluorobenzyl)thieno[3,2-d]pyrimidin-4-amine -   N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   N-(2-(trifluoromethoxy)benzyl)thieno[3,2-d]pyrimidin-4-amine -   N⁴-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N²-isopropylthieno[3,2-d]pyrimidine-2,4-diamine -   N⁴-(2-fluoro-3-methoxybenzyl)-N²-isopropylthieno[3,2-d]pyrimidine-2,4-diamine -   N⁴-(2,6-dichlorobenzyl)-N²-isopropylthieno[3,2-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-(2-(trifluoromethoxy)benzyl)thieno[3,2-d]pyrimidine-2,4-diamine -   N⁴-(2-chloro-6-fluorobenzyl)-N²-isopropylthieno[3,2-d]pyrimidine-2,4-diamine -   N-(2,4-dimethylphenyl)thieno[3,2-d]pyrimidin-4-amine -   N⁴-(2,4-dimethylphenyl)-N²-isopropylthieno[3,2-d]pyrimidine-2,4-diamine -   N⁴-(2-chlorobenzyl)-N²-isopropyl-N²-methylthieno[3,2-d]pyrimidine-2,4-diamine -   1-(3-(thieno[3,2-d]pyrimidin-4-ylamino)propyl)pyrrolidin-2-one -   1-(3-((2-((2-methoxybenzyl)amino)thieno[3,2-d]pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one -   1-(3-((2-(benzyl(methyl)amino)thieno[3,2-d]pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one -   N-(thieno[3,2-d]pyrimidin-4-yl)-2-(trifluoromethyl)benzamide -   N-(1-(2-chlorophenyl)ethyl)thieno[3,2-d]pyrimidin-4-amine -   2-chloro-N-(thieno[3,2-d]pyrimidin-4-yl)benzamide -   N²-(tert-butyl)-N⁴-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidine-2,4-diamine -   N²-(2,2,2     trifluoroethyl)-N⁴-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidine-2,4-diamine -   N²-cyclopropyl-N⁴-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidine-2,4-diamine -   N-methyl-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   N²-isopropyl-N⁴-(2-(trifluoromethyl)phenethyl)thieno[3,2-d]pyrimidine-2,4-diamine -   2-chloro-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   2-chloro-N-(1-(2-chlorophenyl)cyclopropyl)thieno[3,2-d]pyrimidin-4-amine -   N⁴-(1-(2-chlorophenyl)cyclopropyl)-N²-isopropylthieno[3,2-d]pyrimidine-2,4-diamine -   2-chloro-N-methyl-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   N²-isopropyl-N⁴-methyl-N⁴-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidine-2,4-diamine -   N-(3-methoxy-2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   2-chloro-N-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidin-4-amine -   N²-isopropyl-N⁴-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidine-2,4-diamine -   N-ethyl-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   2-methyl-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   2-(trifluoromethyl)-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   2-chloro-N-(2-(trifluoromethyl)benzyl)quinazolin-4-amine -   N²-isopropyl-N⁴-(2-(trifluoromethyl)benzyl)quinazoline-2,4-diamine -   N²-isopropyl-N⁴-(2-(trifluoromethyl)phenyl)thieno[3,2-d]pyrimidine-2,4-diamine -   N-(4-fluoro-2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   N-((3-(trifluoromethyl)pyridin-2-yl)methyl)thieno[3,2-d]pyrimidin-4-amine -   N-methyl-2-(trifluoromethyl)-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   N,2-dimethyl-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   N,6-dimethyl-2-(trifluoromethyl)-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   2-methyl-N-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidin-4-amine -   N,2-dimethyl-N-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidin-4-amine -   2-chloro-N-methyl-N-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidin-4-amine -   2-methoxy-N-methyl-N-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidin-4-amine -   N,2,6-trimethyl-N-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidin-4-amine -   2-(2-methyl-4-(methyl(1-(2-(trifluoromethyl)phenyl)ethyl)amino)thieno[3,2-d]pyrimidin-6-yl)propan-2-ol -   N-(4-fluoro-2-(trifluoromethyl)benzyl)quinazolin-4-amine -   N-(4-fluoro-2-(trifluoromethyl)benzyl)-2-methylquinazolin-4-amine -   4-(methyl(1-(2-(trifluoromethyl)phenyl)ethyl)amino)thieno[3,2-d]pyrimidine-2-carbonitrile -   N-(4-fluoro-2-(trifluoromethyl)benzyl)-N-methylquinazolin-4-amine -   1-(3-((4-((2-(trifluoromethyl)benzyl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)propyl)pyrrolidin-2-one -   N²-(2-(dimethylamino)ethyl)-N⁴-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidine-2,4-diamine -   N²-(2-morpholinoethyl)-N⁴-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidine-2,4-diamine -   N²-(2-(pyrrolidin-1-yl)ethyl)-N⁴-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidine-2,4-diamine -   N²-(2-(4-methylpiperazin-1-yl)ethyl)-N⁴-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidine-2,4-diamine -   2-(pyrrolidin-1-yl)-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   2-morpholino-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   2-(4-methylpiperazin-1-yl)-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   6-iodo-N-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidin-4-amine -   N-(2-(methylsulfonyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   6-phenyl-N-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidin-4-amine -   6-cyclopropyl-N-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidin-4-amine -   6-(1-methyl-1H-pyrazol-4-yl)-N-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidin-4-amine -   4-((1-(2-(trifluoromethyl)phenyl)ethyl)amino)thieno[3,2-d]pyrimidine-6-carbonitrile -   N-((2-(trifluoromethyl)pyridin-3-yl)methyl)thieno[3,2-d]pyrimidin-4-amine -   2-(((2-chlorothieno[3,2-d]pyrimidin-4-yl)amino)methyl)benzonitrile -   7-methyl-N-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidin-4-amine -   7-bromo-N-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidin-4-amine -   N-(2-(trifluoromethyl)benzyl)thieno[2,3-d]pyrimidin-4-amine -   4-((1-(2-(trifluoromethyl)phenyl)ethyl)amino)thieno[3,2-d]pyrimidine-7-carbonitrile -   N²-isopropyl-N⁴-(4-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-(4-(methylsulfonyl)benzyl)quinazoline-2,4-diamine -   N²-isopropyl-N⁴-(4-(trifluoromethyl)benzyl)quinazoline-2,4-diamine -   N²-isopropyl-N⁴-(2-(methylsulfonyl)benzyl)quinazoline-2,4-diamine -   N²-isopropyl-N⁴-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinazoline-2,4-diamine -   N⁴-(4-cyanobenzyl)-N²-isopropylthieno[3,2-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-(2-(methylsulfonyl)benzyl)thieno[3,2-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-(4-(methylsulfonyl)benzyl)thieno[3,2-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-((6-(trifluoromethyl)pyridin-3-yl)methyl)thieno[3,2-d]pyrimidine-2,4-diamine -   N⁴-(4-cyanobenzyl)-N²-isopropylquinazoline-2,4-diamine -   N⁴-(4-cyanobenzyl)-N²-isopropylpyrido[3,2-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-(2-(methylsulfonyl)benzyl)pyrido[3,2-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-(4-(methylsulfonyl)benzyl)pyrido[3,2-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-(4-(trifluoromethyl)benzyl)pyrido[3,2-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[3,2-d]pyrimidine-2,4-diamine -   N⁴-(4-cyanobenzyl)-N²-isopropylpyrido[2,3-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-(2-(methylsulfonyl)benzyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-(4-(methylsulfonyl)benzyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-(4-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-(4-methoxybenzyl)thieno[3,2-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-(2-methoxybenzyl)thieno[3,2-d]pyrimidine-2,4-diamine -   N⁴-(3,4-dimethoxybenzyl)-N²-isopropylthieno[3,2-d]pyrimidine-2,4-diamine -   N⁴-(4-fluorobenzyl)-N²-isopropylquinazoline-2,4-diamine -   N⁴-(2-fluorobenzyl)-N²-isopropylquinazoline-2,4-diamine -   N⁴-(4-chlorobenzyl)-N²-isopropylquinazoline-2,4-diamine -   N⁴-(2-chlorobenzyl)-N²-isopropylquinazoline-2,4-diamine -   N²-isopropyl-N⁴-(4-methoxybenzyl)quinazoline-2,4-diamine -   N²-isopropyl-N⁴-(2-methoxybenzyl)quinazoline-2,4-diamine -   N⁴-(3,4-dimethoxybenzyl)-N²-isopropylquinazoline-2,4-diamine -   N²-(azetidin-3-yl)-N⁴-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-(1-methylazetidin-3-yl)-N⁴-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-methyl-N⁴-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-(oxetan-3-yl)-N⁴-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   2-((methylamino)methyl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   4-((2-(trifluoromethyl)benzyl)amino)pyrido[2,3-d]pyrimidine-2-carboxamide -   N²-(azetidin-3-yl)-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-(1-methylazetidin-3-yl)-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-methyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine     methanesulfonate -   N²-isopropyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)quinazoline-2,4-diamine -   N²-isopropyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[3,2-d]pyrimidine-2,4-diamine -   N²-isopropyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)thieno[3,2-d]pyrimidine-2,4-diamine -   2-((methylamino)methyl)-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   4-((2-(trifluoromethyl)benzyl)amino)thieno[3,2-d]pyrimidine-2-carboxamide -   N²-cyclopropyl-N⁴-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-cyclopropyl-N⁴-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidine-2,4-diamine     methanesulfonate -   4-((2-(trifluoromethyl)benzyl)amino)pyrido[2,3-d]pyrimidin-2-ol -   N²-(oxetan-3-yl)-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-cyclopropyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-cyclopropyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine     methanesulfonate -   N²-isopropyl-N⁴-methyl-N4-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-isopropyl-N²,N⁴-dimethyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-isopropyl-N²-methyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-isopropyl-N²-methyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine     methanesulfonate -   2-(azetidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(isopropylthio)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   N²-isopropyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)-1,8-naphthyridine-2,4-diamine -   N⁴-(2-fluoro-6-(trifluoromethyl)benzyl)-N²-isopropylpyrido[2,3-d]pyrimidine-2,4-diamine -   4-(6-chloro-5-methyl-7-((pyridin-2-ylmethyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)morpholin-3-one -   N²-(tert-butyl)-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N⁴-(2-fluoro-6-(trifluoromethyl)benzyl)-N²,N²-dimethylpyrido[2,3-d]pyrimidine-2,4-diamine -   N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   3-methyl-1-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)azetidin-3-ol -   2-(2-methylazetidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2,2-dimethylazetidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(pyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   N²-cyclopropyl-N²-methyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-isopropyl-N²-methyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)quinazoline-2,4-diamine -   2-methyl-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(isopropylsulfinyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(isopropylsulfonyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-ol -   N-isopropyl-4-(2-(2-(trifluoromethyl)phenyl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-amine -   N-isopropyl-N-methyl-4-(2-(2-(trifluoromethyl)phenyl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-amine -   N-isopropyl-4-(2-(2-(trifluoromethyl)phenyl)piperidin-1-yl)pyrido[2,3-d]pyrimidin-2-amine -   N-isopropyl-N-methyl-4-(2-(2-(trifluoromethyl)phenyl)piperidin-1-yl)pyrido[2,3-d]pyrimidin-2-amine -   N-isopropyl-4-(3-(2-(trifluoromethyl)phenyl)morpholino)pyrido[2,3-d]pyrimidin-2-amine -   N-isopropyl-N-methyl-4-(3-(2-(trifluoromethyl)phenyl)morpholino)pyrido[2,3-d]pyrimidin-2-amine -   N-isopropyl-4-(2-(2-(trifluoromethyl)phenyl)pyrazolidin-1-yl)pyrido[2,3-d]pyrimidin-2-amine -   N-isopropyl-N-methyl-4-(2-(2-(trifluoromethyl)phenyl)pyrazolidin-1-yl)pyrido[2,3-d]pyrimidin-2-amine -   2-((difluoromethyl)thio)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-morpholino-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine     methanesulfonate -   2-(3,3-difluoropyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3,3-difluoropyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine     methanesulfonate -   2-(4-fluoropiperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4,4-difluoropiperidin-1-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4,4-difluoropiperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   N²-isopropyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine     methanesulfonate -   2-(4-chloropiperidin-1-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-chloropiperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-fluoroazetidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3,3-difluoroazetidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-(trifluoromethyl)azetidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   1-(4-fluorophenyl)-3-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)urea -   1-(3-fluorophenyl)-3-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)urea -   1-(2-fluorophenyl)-3-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)urea -   1-ethyl-3-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)urea -   (S)-2-(3-methylmorpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   (S)-2-(3-methylmorpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine     methanesulfonate -   (R)-2-(3-methylmorpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   (S)-2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   (R)-2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-chloropiperidin-1-yl)-4-(2-(2-(trifluoromethyl)phenyl)azetidin-1-yl)pyrido[2,3-d]pyrimidine -   2-(4,4-difluoropiperidin-1-yl)-4-(2-(2-(trifluoromethyl)phenyl)azetidin-1-yl)pyrido[2,3-d]pyrimidine -   3-methyl-4-(4-(2-(2-(trifluoromethyl)phenyl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)morpholine -   2-(3,3-difluoropyrrolidin-1-yl)-4-(2-(2-(trifluoromethyl)phenyl)azetidin-1-yl)pyrido[2,3-d]pyrimidine -   2-(3-(trifluoromethyl)azetidin-1-yl)-4-(2-(2-(trifluoromethyl)phenyl)azetidin-1-yl)pyrido[2,3-d]pyrimidine -   2-(4-chloropiperidin-1-yl)-4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidine -   2-(4,4-difluoropiperidin-1-yl)-4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidine -   3-methyl-4-(4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)morpholine -   2-(3,3-difluoropyrrolidin-1-yl)-4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidine -   2-(3-(trifluoromethyl)azetidin-1-yl)-4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidine -   2-((4-chloropiperidin-1-yl)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((4,4-difluoropiperidin-1-yl)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((3-methylmorpholino)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((3,3-difluoropyrrolidin-1-yl)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((3-(trifluoromethyl)azetidin-1-yl)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((4-chloropiperidin-1-yl)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((4,4-difluoropiperidin-1-yl)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((3-methylmorpholino)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((3,3-difluoropyrrolidin-1-yl)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((3-(trifluoromethyl)azetidin-1-yl)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-(methylsulfonyl)piperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4,4-dimethylpiperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   1-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperidine-4-carbonitrile -   2-(4-(trifluoromethyl)piperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyr-     imidin-4-amine -   N-((2-(trifluoromethyl)pyridin-3-yl)methyl)-2-(3-(trifluoromethyl)pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin-4-amine -   1-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)azetidine-3-carbonitrile -   1-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)pyrrolidine-2-carbonitrile -   2-(2,2-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3,3-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-fluoropyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-(methylsulfonyl)piperidin-1-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4,4-dimethylpiperidin-1-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   1-(4-((2-(trifluoromethyl)benzyl)amino)pyrido[2,3-d]pyrimidin-2-yl)azetidine-3-carbonitrile -   2-(3,3-dimethylmorpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2,2-dimethylmorpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-methylmorpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-(trifluoromethyl)piperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   4-methyl-1-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperidine-4-carbonitrile -   1-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperidine-3-carbonitrile -   2-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine     methanesulfonate -   2-(3-cyclopropylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((6S)-2,6-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-oxa-7-azaspiro[2.5]octan-7-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   4-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)morpholine-2-carbonitrile -   2-(3-(fluoromethyl)piperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyri-     midin-4-amine -   2-(2-(trifluoromethyl)piperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   (2-(trifluoromethyl)pyridin-3-yl)metha     4-methyl-1-(4-((2-(trifluoromethyl)benzyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperidine-4-carbonitrile -   1-(4-((2-(trifluoromethyl)benzyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperidine-3-carbonitrile -   2-(3-(methylsulfonyl)pyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   N-((2-(trifluoromethyl)pyridin-3-yl)methyl)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-chloropyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   N-(2-(trifluoromethyl)benzyl)-2-(3-(trifluoromethyl)pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((6S)-2,6-dimethylmorpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-isopropylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((2R,3R)-2,3-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((2S,5R)-2,5-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(6-oxa-9-azaspiro[4.5]decan-9-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-(trifluoromethoxy)piperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-(trifluoromethoxy)piperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine     methanesulfonate -   2-(3-(difluoromethyl)azetidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((3R)-3,5-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-(difluoromethyl)azetidin-1-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((3R)-3,5-dimethylmorpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-cyclopropylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((2S,5S)-2,5-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   (R)-2-(3-(difluoromethoxy)pyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   (S)-2-(3-(difluoromethoxy)pyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-(difluoromethyl)morpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   4-(4-((2-(trifluoromethyl)benzyl)amino)pyrido[2,3-d]pyrimidin-2-yl)morpholine-2-carbonitrile -   2-(2-(difluoromethyl)morpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(8-oxa-5-azaspiro[3.5]nonan-5-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(9-oxa-6-azaspiro[4.5]decan-6-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((2R,3S)-2,3-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   (3R)-3-methyl-4-(4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)morpholine -   (3S)-3-methyl-4-(4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)morpholine -   (3R)-3-methyl-4-(4-(2-(2-(trifluoromethyl)phenyl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)morpholine -   (3S)-3-methyl-4-(4-(2-(2-(trifluoromethyl)phenyl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)morpholine -   2-(3-(difluoromethoxy)piperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2,2,6,6-tetrafluoromorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-azaspiro[2.5]octan-4-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-(trifluoromethoxy)pyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(5-azaspiro[3.4]octan-5-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-((trifluoromethoxy)methyl)pyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((3R)-3,5-dimethylmorpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   6-fluoro-2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   6-methoxy-2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   7-methoxy-2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrimido[4,5-d]pyrimidin-4-amine -   2-(3-methylmorpholino)-N-(2-(trifluoromethyl)benzyl)pyrimido[4,5-d]pyrimidin-4-amine -   5-methoxy-2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   6,7-dimethoxy-2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pteridin-4-amine -   2-(3-methylmorpholino)-N-(2-(trifluoromethyl)benzyl)pteridin-4-amine -   2-(3-methylmorpholino)-7-(2-morpholinoethoxy)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-methylmorpholino)-7-(2-morpholinoethoxy)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)     quinazolin-4-amine.

77. A compound, or salt or solvate thereof, according to paragraph 76 selected from:

-   (3R)-3-methyl-4-(4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)morpholine -   2-(3-(difluoromethyl)azetidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((2R,3R)-2,3-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-isopropylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   N-(2-(trifluoromethyl)benzyl)-2-(3-(trifluoromethyl)pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-cyclopropylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   1-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperidine-3-carbonitrile -   1-(4-((2-(trifluoromethyl)benzyl)amino)pyrido[2,3-d]pyrimidin-2-yl)azetidine-3-carbonitrile -   2-(4,4-dimethylpiperidin-1-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-fluoropyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   1-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperidine-4-carbonitrile -   2-(3-(trifluoromethyl)azetidin-1-yl)-4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidine -   3-methyl-4-(4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)morpholine -   (S)-2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-(trifluoromethyl)azetidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-chloropiperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-chloropiperidin-1-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   N²-isopropyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine     methanesulfonate -   2-(4,4-difluoropiperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-fluoropiperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3,3-difluoropyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine     methanesulfonate -   2-(3,3-difluoropyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine     methanesulfonate -   2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   N-isopropyl-4-(2-(2-(trifluoromethyl)phenyl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-amine -   N²-cyclopropyl-N²-methyl-N4-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   2-(2,2-dimethylazetidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   N²-(tert-butyl)-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-isopropyl-N²,N⁴-dimethyl-N4-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-cyclopropyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine     methanesulfonate -   N²-cyclopropyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-cyclopropyl-N⁴-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N,2-dimethyl-N-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidin-4-amine -   N-ethyl-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   N²-isopropyl-N⁴-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidine-2,4-diamine -   2-chloro-N-methyl-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   N²-isopropyl-N⁴-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidine-2,4-diamine     methanesulfonate -   N²-isopropyl-N⁴-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-isopropyl-N²-methyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-isopropyl-N²-methyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine     methanesulfonate -   N⁴-(2-fluoro-6-(trifluoromethyl)benzyl)-N²-isopropylpyrido[2,3-d]pyrimidine-2,4-diamine -   2-(2-methylazetidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(pyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   N-isopropyl-N-methyl-4-(2-(2-(trifluoromethyl)phenyl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-amine -   2-(4,4-difluoropiperidin-1-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   3-methyl-4-(4-(2-(2-(trifluoromethyl)phenyl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)morpholine -   2-(4,4-difluoropiperidin-1-yl)-4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidine -   2-(3,3-difluoropyrrolidin-1-yl)-4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidine -   2-(4-(trifluoromethyl)piperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2,2-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3,3-dimethylmorpholino)-N-((2- (trifluoromethyl)     pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-methylmorpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   4-methyl-1-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperidine-4-carbonitrile -   2-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine     methanesulfonate -   2-(2-(trifluoromethyl)piperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   1-(4-((2-(trifluoromethyl)benzyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperidine-3-carbonitrile -   2-((2S,5R)-2,5-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(6-oxa-9-azaspiro[4.5]decan-9-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((3R)-3,5-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-cyclopropylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((2S,5S)-2,5-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   (R)-2-(3-(difluoromethoxy)pyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   (S)-2-(3-(difluoromethoxy)pyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-(difluoromethyl)morpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   4-(4-((2-(trifluoromethyl)benzyl)amino)pyrido[2,3-d]pyrimidin-2-yl)morpholine-2-carbonitrile -   2-((2R,3S)-2,3-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   (3S)-3-methyl-4-(4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)morpholine -   (3R)-3-methyl-4-(4-(2-(2-(trifluoromethyl)phenyl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)morpholine -   (3S)-3-methyl-4-(4-(2-(2-(trifluoromethyl)phenyl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)morpholine -   2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   (S)-2-(3-methylmorpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   (S)-2-(3-methylmorpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine     methanesulfonate -   2-(4-chloropiperidin-1-yl)-4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidine -   N-((2-(trifluoromethyl)pyridin-3-yl)methyl)-2-(3-(trifluoromethyl)pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2,2-dimethylmorpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-oxa-7-azaspiro[2.5]octan-7-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-(fluoromethyl)piperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   (2-(trifluoromethyl)pyridin-3-yl)metha     4-methyl-1-(4-((2-(trifluoromethyl)benzyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperidine-4-carbonitrile -   N-((2-(trifluoromethyl)pyridin-3-yl)methyl)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-chloropyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-(trifluoromethoxy)piperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-(trifluoromethoxy)piperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine     methanesulfonate -   2-(3-(difluoromethyl)azetidin-1-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-(difluoromethyl)morpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-azaspiro[2.5]octan-4-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-(trifluoromethoxy)pyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(5-azaspiro[3.4]octan-5-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-((trifluoromethoxy)methyl)pyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((3R)-3,5-dimethylmorpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine.

78. A pharmaceutical composition comprising a compound according to paragraphs 1 to 77, or a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

79. A compound according to any one of paragraphs 1 to 77, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.

80. A combination comprising a compound according to any one of paragraphs 1 to 77, or a pharmaceutically acceptable salt or solvate thereof, with one or more additional therapeutic agents.

81. A compound of Formula II:

or a salt or solvate thereof, wherein,

-   A represents a fused aromatic ring selected from,

-   

-   

-   X¹, X² and X³ are independently selected from N and CH;

-   Q is a group selected from an C₃₋₁₁cycloalkyl optionally substituted     by one or more R^(b), 3-15 membered heterocycloalkyl optionally     substituted by one or more R^(b), C₆₋₁₁ aryl group optionally     substituted with by one or more R^(b), 5-15 membered heteroaryl     optionally substituted by one or more R^(b);

-   R⁶ is selected from hydrogen and C₁₋₆ alkyl;

-   R⁷ and R⁷′ are independently selected from hydrogen, C₃₋₆     cycloalkyl, C₁₋₆ alkyl, where said C₃₋₆ cycloalkyl and C₁₋₆ alkyl     are optionally substituted by one or more R^(a); or

-   R⁷ and R⁷′, together with the carbon to which they are attached form     a 3-7 membered cycloalkyl ring, optionally substituted with one or     more R^(a), or R⁷ and R⁷′, together with the carbon to which they     are attached form a carbonyl group; or

-   R⁶and R⁷, together with the atoms to which they are attached form a     3-7 membered heterocyclic ring, optionally substituted with one or     more R^(a);

-   n is a number selected from 0, 1, 2 and 3

-   R² is selected from hydrogen, hydroxyl, halogen, —CN, —C(═O)R^(d),     —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d),     -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)R^(d),     —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d),     —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d) —OC(═O)R^(d),     —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)R^(d), —S(═O)₂R^(d),     —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d),     —OS(═O)₂NR^(c)R^(d), —S(═O)₂NR^(c)R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl     optionally substituted by one or more R^(e), C₂₋₆alkenyl optionally     substituted by one or more R^(e), C₂₋₆alkynyl optionally substituted     by one or more R^(e), C₆₋₁₁aryl optionally substituted by one or     more R^(e), (C₇₋₁₆)alkylaryl optionally substituted by one or more     R^(e), C₃₋₁₁cycloalkyl optionally substituted by one or more R^(e),     (C₄₋₁₇)cycloalkylalkyl optionally substituted by one or more R^(e),     3-15 membered heterocycloalkyl optionally substituted by one or more     R^(e), 4-21 membered alkylheterocycloalkyl optionally substituted by     one or more R^(e), 5-15 membered heteroaryl optionally substituted     by one or more R^(e), and 6-21 membered alkylheteroaryl optionally     substituted by one or more R^(e);

-   each R^(a) is independently selected from hydroxyl, halogen, CN,     C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7     membered heterocycloalkyl, wherein said C₃₋₆ cycloalkyl and 3-7     membered heterocycloalkyl are optionally substituted with one or     more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl,     C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁-₆ alkyl;

-   each R^(b) and R^(e) is independently selected from hydroxyl, =O,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, O-C₁₋₆     alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, —C(═O)R^(d),     —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d),     —NR^(c)C(═O)R^(d), —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d),     —NR^(c)S(═O)₂R^(d), —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d),     —OC(═O)R^(d), —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)₂R^(d),     —S(═O)R^(d), —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d),     —S(═O)NR^(c)R^(d), —OS(═O)₂NR^(c)R^(d), and —S(═O)₂NR^(c)R^(d),     where said C₃₋₆ cycloalkyl, C₁₋₆ alkyl, and 3-7 membered     heterocycloalkyl are optionally substituted with one or more groups     selected from hydroxyl, halogen, =O, CN, C₁₋₆ haloalkyl, C₁₋₆     haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl;

-   each R^(c) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆     alkyl;

-   each R^(d) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, 3-7 membered heterocycloalkyl, C₃₋₆     cycloalkyl, C₁₋₆ alkyl, O-C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said     C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆     cycloalkyl are optionally substituted with one or more groups     selected from hydroxyl, halogen, CN, amino, C₁₋₆ haloalkyl, C₃₋₆     cycloalkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl, C₁₋₆ alkyl     and O-C₁₋₆ alkyl; or

-   R^(c) and R^(d), when attached to the same atom, together with the     atom to which they are attached form a 3-7 membered ring, optionally     containing one or more for heteroatoms selected from O, NH and S,     and wherein said ring is optionally substituted with one or more     R^(a);

-   R³, R⁴ and R⁵ are independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, phenyl and     cyclopropyl, wherein said C₁₋₆ alkyl, phenyl and cyclopropyl are     optionally substituted by one or more R^(a);

-   or a pharmaceutically acceptable salt or solvate thereof, for use in     the treatment or prevention of a filarial worm infection.

82. A compound for use according to paragraph 81, wherein the infection is with one or more filarial worms selected from Wuchereria bancrofti, Brugia malayi, Brugia timori and Onchocerca volvulus.

83. A compound of Formula II:

or a salt or solvate thereof, wherein,

-   A represents a fused aromatic ring selected from,

-   

-   

-   X¹, X² and X³ are independently selected from N and CH;

-   Q is a group selected from an C₃₋₁₁cycloalkyl optionally substituted     by one or more R^(b), 3-15 membered heterocycloalkyl optionally     substituted by one or more R^(b), C₆₋₁₁ aryl group optionally     substituted with by one or more R^(b), 5-15 membered heteroaryl     optionally substituted by one or more R^(b);

-   R⁶ is selected from hydrogen and C₁₋₆ alkyl;

-   R⁷ and R⁷′ are independently selected from hydrogen, C₃₋₆     cycloalkyl, C₁₋₆ alkyl, where said C₃₋₆ cycloalkyl and C₁₋₆ alkyl     are optionally substituted by one or more R^(a); or

-   R⁷ and R⁷′, together with the carbon to which they are attached form     a 3-7 membered cycloalkyl ring, optionally substituted with one or     more R^(a), or R⁷ and R⁷′, together with the carbon to which they     are attached form a carbonyl group; or

-   R⁶ and R⁷, together with the atoms to which they are attached form a     3-7 membered heterocyclic ring, optionally substituted with one or     more R^(a);

-   n is a number selected from 0, 1, 2 and 3

-   R² is selected from hydrogen, hydroxyl, halogen, —CN, —C(═O)R^(d),     —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d),     -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)R^(d),     —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d),     —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d) —OC(═O)R^(d),     —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)R^(d), —S(═O)₂R^(d),     —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d),     —OS(═O)₂NR^(c)R^(d), —S(═O)₂NR^(c)R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl     optionally substituted by one or more R^(e), C₂₋₆alkenyl optionally     substituted by one or more R^(e), C₂₋₆alkynyl optionally substituted     by one or more R^(e), C₆₋₁₁aryl optionally substituted by one or     more R^(e), (C₇₋₁₆)alkylaryl optionally substituted by one or more     R^(e), C₃₋₁₁cycloalkyl optionally substituted by one or more R^(e),     (C₄₋₁₇)cycloalkylalkyl optionally substituted by one or more R^(e),     3-15 membered heterocycloalkyl optionally substituted by one or more     R^(e), 4-21 membered alkylheterocycloalkyl optionally substituted by     one or more R^(e), 5-15 membered heteroaryl optionally substituted     by one or more R^(e), and 6-21 membered alkylheteroaryl optionally     substituted by one or more R^(e);

-   each R^(a) is independently selected from hydroxyl, halogen, CN,     C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7     membered heterocycloalkyl, wherein said C₃₋₆ cycloalkyl and 3-7     membered heterocycloalkyl are optionally substituted with one or     more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl,     C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁-₆ alkyl;

-   each R^(b) and R^(e) is independently selected from hydroxyl, =O,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, O-C₁₋₆     alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, —C(═O)R^(d),     —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d),     —NR^(c)C(═O)R^(d), —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d),     —NR^(c)S(═O)₂R^(d), —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d),     —OC(═O)R^(d), —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)₂R^(d),     —S(═O)R^(d), —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d),     —S(═O)NR^(c)R^(d), —OS(═O)₂NR^(c)R^(d), and —S(═O)₂NR^(c)R^(d),     where said C₃₋₆ cycloalkyl, C₁₋₆ alkyl, and 3-7 membered     heterocycloalkyl are optionally substituted with one or more groups     selected from hydroxyl, halogen, =O, CN, C₁₋₆ haloalkyl, C₁₋₆     haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl;

-   each R^(c) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆     alkyl;

-   each R^(d) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, 3-7 membered heterocycloalkyl, C₃₋₆     cycloalkyl, C₁₋₆ alkyl, O-C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said     C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆     cycloalkyl are optionally substituted with one or more groups     selected from hydroxyl, halogen, CN, amino, C₁₋₆ haloalkyl, C₃₋₆     cycloalkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl, C₁₋₆ alkyl     and O-C₁₋₆ alkyl; or

-   R^(c) and R^(d), when attached to the same atom, together with the     atom to which they are attached form a 3-7 membered ring, optionally     containing one or more for heteroatoms selected from O, NH and S,     and wherein said ring is optionally substituted with one or more     R^(a);

-   R³, R⁴ and R⁵ are independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, phenyl and     cyclopropyl, wherein said C₁₋₆ alkyl, phenyl and cyclopropyl are     optionally substituted by one or more R^(a);

-   or a pharmaceutically acceptable salt or solvate thereof, for use in     the treatment or prevention of a disease or condition mediated by a     filarial worm infection.

84. A compound for use according to paragraph 83, wherein the disease or condition is mediated by infection with one or more of Wuchereria bancrofti, Brugia malayi, Brugia timori and Onchocerca volvulus.

85. A compound for use according to paragraph 83, wherein the disease or condition is selected from onchocerciasis or lymphatic filariasis.

86. A compound of Formula II:

or a salt or solvate thereof, wherein,

-   A represents a fused aromatic ring selected from,

-   

-   

-   X¹, X² and X³ are independently selected from N and CH;

-   Q is a group selected from an C₃₋₁₁cycloalkyl optionally substituted     by one or more R^(b), 3-15 membered heterocycloalkyl optionally     substituted by one or more R^(b), C₆₋₁₁ aryl group optionally     substituted with by one or more R^(b), 5-15 membered heteroaryl     optionally substituted by one or more R^(b);

-   R⁶ is selected from hydrogen and C₁₋₆ alkyl;

-   R⁷ and R⁷′ are independently selected from hydrogen, C₃₋₆     cycloalkyl, C₁₋₆ alkyl, where said C₃₋₆ cycloalkyl and C₁₋₆ alkyl     are optionally substituted by one or more R^(a); or

-   R⁷ and R⁷′, together with the carbon to which they are attached form     a 3-7 membered cycloalkyl ring, optionally substituted with one or     more R^(a), or R⁷ and R⁷′, together with the carbon to which they     are attached form a carbonyl group; or

-   R⁶ and R⁷, together with the atoms to which they are attached form a     3-7 membered heterocyclic ring, optionally substituted with one or     more R^(a);

-   n is a number selected from 0, 1, 2 and 3

-   R² is selected from hydrogen, hydroxyl, halogen, —CN, —C(═O)R^(d),     —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d),     -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)R^(d),     —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d),     —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d) —OC(═O)R^(d),     —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)R^(d), —S(═O)₂R^(d),     —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d),     —OS(═O)₂NR^(c)R^(d), —S(═O)₂NR^(c)R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl     optionally substituted by one or more R^(e), C₂₋₆alkenyl optionally     substituted by one or more R^(e), C₂₋₆alkynyl optionally substituted     by one or more R^(e), C₆₋₁₁aryl optionally substituted by one or     more R^(e), (C₇₋₁₆)alkylaryl optionally substituted by one or more     R^(e), C₃₋₁₁cycloalkyl optionally substituted by one or more R^(e),     (C₄₋₁₇)cycloalkylalkyl optionally substituted by one or more R^(e),     3-15 membered heterocycloalkyl optionally substituted by one or more     R^(e), 4-21 membered alkylheterocycloalkyl optionally substituted by     one or more R^(e), 5-15 membered heteroaryl optionally substituted     by one or more R^(e), and 6-21 membered alkylheteroaryl optionally     substituted by one or more R^(e);

-   each R^(a) is independently selected from hydroxyl, halogen, CN,     C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7     membered heterocycloalkyl, wherein said C₃₋₆ cycloalkyl and 3-7     membered heterocycloalkyl are optionally substituted with one or     more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl,     C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁-₆ alkyl;

-   each R^(b) and R^(e) is independently selected from hydroxyl, =O,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, O-C₁₋₆     alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, —C(═O)R^(d),     —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d),     —NR^(c)C(═O)R^(d), —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d),     —NR^(c)S(═O)₂R^(d), —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d),     —OC(═O)R^(d), —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)₂R^(d),     —S(═O)R^(d), —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)20R^(d),     —S(═O)NR^(c)R^(d), —OS(═O)₂NR^(c)R^(d), and —S(═O)₂NR^(c)R^(d),     where said C₃₋₆ cycloalkyl, C₁₋₆ alkyl, and 3-7 membered     heterocycloalkyl are optionally substituted with one or more groups     selected from hydroxyl, halogen, =O, CN, C₁₋₆ haloalkyl, C₁₋₆     haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl;

-   each R^(c) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆     alkyl;

-   each R^(d) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, 3-7 membered heterocycloalkyl, C₃₋₆     cycloalkyl, C₁₋₆ alkyl, O-C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said     C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆     cycloalkyl are optionally substituted with one or more groups     selected from hydroxyl, halogen, CN, amino, C₁₋₆ haloalkyl, C₃₋₆     cycloalkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl, C₁₋₆ alkyl     and O-C₁₋₆ alkyl; or

-   R^(c) and R^(d), when attached to the same atom, together with the     atom to which they are attached form a 3-7 membered ring, optionally     containing one or more for heteroatoms selected from O, NH and S,     and wherein said ring is optionally substituted with one or more     R^(a);

-   R³, R⁴ and R⁵ are independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, phenyl and     cyclopropyl, wherein said C₁₋₆ alkyl, phenyl and cyclopropyl are     optionally substituted by one or more R^(a);

-   or a pharmaceutically acceptable salt or solvate thereof, for use in     the treatment of a microbial infection.

87. A compound for use according to paragraph 86 wherein the microbial infection is a bacterial infection.

88. A compound for use according to paragraph 87 wherein the bacterial infection is Wolbachia infection.

89. A method of treating or preventing a filarial worm infection in a subject, said method comprising administering to a subject a therapeutically effective amount of a compound of Formula II:

or a salt or solvate thereof, wherein,

-   A represents a fused aromatic ring selected from,

-   

-   

-   X¹, X² and X³ are independently selected from N and CH;

-   Q is a group selected from an C₃₋₁₁cycloalkyl optionally substituted     by one or more R^(b), 3-15 membered heterocycloalkyl optionally     substituted by one or more R^(b), C₆₋₁₁ aryl group optionally     substituted with by one or more R^(b), 5-15 membered heteroaryl     optionally substituted by one or more R^(b);

-   R⁶ is selected from hydrogen and C₁₋₆ alkyl;

-   R⁷ and R⁷′ are independently selected from hydrogen, C₃₋₆     cycloalkyl, C₁₋₆ alkyl, where said C₃₋₆ cycloalkyl and C₁₋₆ alkyl     are optionally substituted by one or more R^(a); or

-   R⁷ and R⁷′, together with the carbon to which they are attached form     a 3-7 membered cycloalkyl ring, optionally substituted with one or     more R^(a), or R⁷ and R⁷′, together with the carbon to which they     are attached form a carbonyl group; or

-   R⁶ and R⁷, together with the atoms to which they are attached form a     3-7 membered heterocyclic ring, optionally substituted with one or     more R^(a);

-   n is a number selected from 0, 1, 2 and 3

-   R² is selected from hydrogen, hydroxyl, halogen, —CN, —C(═O)R^(d),     —C(═O)OR^(d), -C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d),     -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)R^(d),     —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d),     —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d) —OC(═O)R^(d),     —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)R^(d), —S(═O)₂R^(d),     —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d),     —OS(═O)₂NR^(c)R^(d), —S(═O)₂NR^(c)R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl     optionally substituted by one or more R^(e), C₂₋₆alkenyl optionally     substituted by one or more R^(e), C₂₋₆alkynyl optionally substituted     by one or more R^(e), C₆₋₁₁aryl optionally substituted by one or     more R^(e), (C₇₋₁₆)alkylaryl optionally substituted by one or more     R^(e), C₃₋₁₁cycloalkyl optionally substituted by one or more R^(e),     (C₄₋₁₇)cycloalkylalkyl optionally substituted by one or more R^(e),     3-15 membered heterocycloalkyl optionally substituted by one or more     R^(e), 4-21 membered alkylheterocycloalkyl optionally substituted by     one or more R^(e), 5-15 membered heteroaryl optionally substituted     by one or more R^(e), and 6-21 membered alkylheteroaryl optionally     substituted by one or more R^(e);

-   each R^(a) is independently selected from hydroxyl, halogen, CN,     C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7     membered heterocycloalkyl, wherein said C₃₋₆ cycloalkyl and 3-7     membered heterocycloalkyl are optionally substituted with one or     more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl,     C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁-₆ alkyl;

-   each R^(b) and R^(e) is independently selected from hydroxyl, =O,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, O-C₁₋₆     alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, —C(═O)R^(d),     —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d),     —NR^(c)C(═O)R^(d), —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d),     —NR^(c)S(═O)₂R^(d), —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d),     —OC(═O)R^(d), —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)₂R^(d),     —S(═O)R^(d), —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d),     —S(═O)NR^(c)R^(d), —OS(═O)₂NR^(c)R^(d), and —S(═O)₂NR^(c)R^(d),     where said C₃₋₆ cycloalkyl, C₁₋₆ alkyl, and 3-7 membered     heterocycloalkyl are optionally substituted with one or more groups     selected from hydroxyl, halogen, =O, CN, C₁₋₆ haloalkyl, C₁₋₆     haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl;

-   each R^(c) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆     alkyl;

-   each R^(d) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, 3-7 membered heterocycloalkyl, C₃₋₆     cycloalkyl, C₁₋₆ alkyl, O-C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said     C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆     cycloalkyl are optionally substituted with one or more groups     selected from hydroxyl, halogen, CN, amino, C₁₋₆ haloalkyl, C₃₋₆     cycloalkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl, C₁₋₆ alkyl     and O-C₁₋₆ alkyl; or

-   R^(c) and R^(d), when attached to the same atom, together with the     atom to which they are attached form a 3-7 membered ring, optionally     containing one or more for heteroatoms selected from O, NH and S,     and wherein said ring is optionally substituted with one or more     R^(a);

-   R³, R⁴ and R⁵ are independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, phenyl and     cyclopropyl, wherein said C₁₋₆ alkyl, phenyl and cyclopropyl are     optionally substituted by one or more R^(a);

-   or a pharmaceutically acceptable salt or solvate thereof.

90. A method according to paragraph 89 wherein the infection is with one or more filarial worms selected from Wuchereria bancrofti, Brugia malayi, Brugia timori and Onchocerca volvulus.

91. A method of treating or preventing a disease or condition mediated by a filarial worm infection, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula II:

or a salt or solvate thereof, wherein,

-   A represents a fused aromatic ring selected from,

-   

-   

-   X¹, X² and X³ are independently selected from N and CH;

-   Q is a group selected from an C₃₋₁₁cycloalkyl optionally substituted     by one or more R^(b), 3-15 membered heterocycloalkyl optionally     substituted by one or more R^(b), C₆₋₁₁ aryl group optionally     substituted with by one or more R^(b), 5-15 membered heteroaryl     optionally substituted by one or more R^(b);

-   R⁶ is selected from hydrogen and C₁₋₆ alkyl;

-   R⁷ and R⁷′ are independently selected from hydrogen, C₃₋₆     cycloalkyl, C₁₋₆ alkyl, where said C₃₋₆ cycloalkyl and C₁₋₆ alkyl     are optionally substituted by one or more R^(a); or

-   R⁷ and R⁷′, together with the carbon to which they are attached form     a 3-7 membered cycloalkyl ring, optionally substituted with one or     more R^(a), or R⁷ and R⁷′, together with the carbon to which they     are attached form a carbonyl group; or

-   R⁶ and R⁷, together with the atoms to which they are attached form a     3-7 membered heterocyclic ring, optionally substituted with one or     more R^(a);

-   n is a number selected from 0, 1, 2 and 3

-   R² is selected from hydrogen, hydroxyl, halogen, —CN, —C(═O)R^(d),     —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d),     -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)R^(d),     —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d),     —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d) —OC(═O)R^(d),     —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)R^(d), —S(═O)₂R^(d),     —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d),     —OS(═O)₂NR^(c)R^(d), —S(═O)₂NR^(c)R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl     optionally substituted by one or more R^(e), C₂₋₆alkenyl optionally     substituted by one or more R^(e), C₂₋₆alkynyl optionally substituted     by one or more R^(e), C₆₋₁₁aryl optionally substituted by one or     more R^(e), (C₇₋₁₆)alkylaryl optionally substituted by one or more     R^(e), C₃₋₁₁cycloalkyl optionally substituted by one or more R^(e),     (C₄₋₁₇)cycloalkylalkyl optionally substituted by one or more R^(e),     3-15 membered heterocycloalkyl optionally substituted by one or more     R^(e), 4-21 membered alkylheterocycloalkyl optionally substituted by     one or more R^(e), 5-15 membered heteroaryl optionally substituted     by one or more R^(e), and 6-21 membered alkylheteroaryl optionally     substituted by one or more R^(e);

-   each R^(a) is independently selected from hydroxyl, halogen, CN,     C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7     membered heterocycloalkyl, wherein said C₃₋₆ cycloalkyl and 3-7     membered heterocycloalkyl are optionally substituted with one or     more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl,     C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁-₆ alkyl;

-   each R^(b) and R^(e) is independently selected from hydroxyl, =O,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, O-C₁₋₆     alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, —C(═O)R^(d),     —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d),     —NR^(c)C(═O)R^(d), —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d),     —NR^(c)S(═O)₂R^(d), —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d),     —OC(═O)R^(d), —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)₂R^(d),     —S(═O)R^(d), —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)20R^(d),     —S(═O)NR^(c)R^(d), —OS(═O)₂NR^(c)R^(d), and —S(═O)₂NR^(c)R^(d),     where said C₃₋₆ cycloalkyl, C₁₋₆ alkyl, and 3-7 membered     heterocycloalkyl are optionally substituted with one or more groups     selected from hydroxyl, halogen, =O, CN, C₁₋₆ haloalkyl, C₁₋₆     haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl;

-   each R^(c) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆     alkyl;

-   each R^(d) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, 3-7 membered heterocycloalkyl, C₃₋₆     cycloalkyl, C₁₋₆ alkyl, O-C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said     C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆     cycloalkyl are optionally substituted with one or more groups     selected from hydroxyl, halogen, CN, amino, C₁₋₆ haloalkyl, C₃₋₆     cycloalkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl, C₁₋₆ alkyl     and O-C₁₋₆ alkyl; or

-   R^(c) and R^(d), when attached to the same atom, together with the     atom to which they are attached form a 3-7 membered ring, optionally     containing one or more for heteroatoms selected from O, NH and S,     and wherein said ring is optionally substituted with one or more     R^(a);

-   R³, R⁴ and R⁵ are independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, phenyl and     cyclopropyl, wherein said C₁₋₆ alkyl, phenyl and cyclopropyl are     optionally substituted by one or more R^(a);

-   or a pharmaceutically acceptable salt or solvate thereof.

92. A method according to paragraph 91 wherein the disease or condition is mediated by infection with one or more of Wuchereria bancrofti, Brugia malayi, Brugia timori and Onchocerca volvulus.

93. The method of any one of paragraphs 91 and 92, wherein the disease or condition is selected from onchocerciasis or lymphatic filariasis.

94. A method of treating a microbial infection, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula II:

or a salt or solvate thereof, wherein,

-   A represents a fused aromatic ring selected from,

-   

-   

-   X¹, X² and X³ are independently selected from N and CH;

-   Q is a group selected from an C₃₋₁₁cycloalkyl optionally substituted     by one or more R^(b), 3-15 membered heterocycloalkyl optionally     substituted by one or more R^(b), C₆₋₁₁ aryl group optionally     substituted with by one or more R^(b), 5-15 membered heteroaryl     optionally substituted by one or more R^(b);

-   R⁶ is selected from hydrogen and C₁₋₆ alkyl;

-   R⁷ and R⁷′ are independently selected from hydrogen, C₃₋₆     cycloalkyl, C₁₋₆ alkyl, where said C₃₋₆ cycloalkyl and C₁₋₆ alkyl     are optionally substituted by one or more R^(a); or

-   R⁷ and R⁷′, together with the carbon to which they are attached form     a 3-7 membered cycloalkyl ring, optionally substituted with one or     more R^(a), or R⁷ and R⁷′, together with the carbon to which they     are attached form a carbonyl group; or

-   R⁶ and R⁷, together with the atoms to which they are attached form a     3-7 membered heterocyclic ring, optionally substituted with one or     more R^(a);

-   n is a number selected from 0, 1, 2 and 3

-   R² is selected from hydrogen, hydroxyl, halogen, —CN, —C(═O)R^(d),     —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d),     -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)R^(d),     —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d),     —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d) —OC(═O)R^(d),     —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)R^(d), —S(═O)₂R^(d),     —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d),     —OS(═O)₂NR^(c)R^(d), —S(═O)₂NR^(c)R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl     optionally substituted by one or more R^(e), C₂₋₆alkenyl optionally     substituted by one or more R^(e), C₂₋₆alkynyl optionally substituted     by one or more R^(e), C₆₋₁₁aryl optionally substituted by one or     more R^(e), (C₇₋₁₆)alkylaryl optionally substituted by one or more     R^(e), C₃₋₁₁cycloalkyl optionally substituted by one or more R^(e),     (C₄₋₁₇)cycloalkylalkyl optionally substituted by one or more R^(e),     3-15 membered heterocycloalkyl optionally substituted by one or more     R^(e), 4-21 membered alkylheterocycloalkyl optionally substituted by     one or more R^(e), 5-15 membered heteroaryl optionally substituted     by one or more R^(e), and 6-21 membered alkylheteroaryl optionally     substituted by one or more R^(e);

-   each R^(a) is independently selected from hydroxyl, halogen, CN,     C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7     membered heterocycloalkyl, wherein said C₃₋₆ cycloalkyl and 3-7     membered heterocycloalkyl are optionally substituted with one or     more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl,     C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁-₆ alkyl;

-   each R^(b) and R^(e) is independently selected from hydroxyl, =O,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, O-C₁₋₆     alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, —C(═O)R^(d),     —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d),     —NR^(c)C(═O)R^(d), —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d),     —NR^(c)S(═O)₂R^(d), —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d),     —OC(═O)R^(d), —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)₂R^(d),     —S(═O)R^(d), —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d),     —S(═O)NR^(c)R^(d), —OS(═O)₂NR^(c)R^(d), and —S(═O)₂NR^(c)R^(d),     where said C₃₋₆ cycloalkyl, C₁₋₆ alkyl, and 3-7 membered     heterocycloalkyl are optionally substituted with one or more groups     selected from hydroxyl, halogen, =O, CN, C₁₋₆ haloalkyl, C₁₋₆     haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl;

-   each R^(c) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆     alkyl;

-   each R^(d) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, 3-7 membered heterocycloalkyl, C₃₋₆     cycloalkyl, C₁₋₆ alkyl, O-C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said     C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆     cycloalkyl are optionally substituted with one or more groups     selected from hydroxyl, halogen, CN, amino, C₁₋₆ haloalkyl, C₃₋₆     cycloalkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl, C₁₋₆ alkyl     and O-C₁₋₆ alkyl; or

-   R^(c) and R^(d), when attached to the same atom, together with the     atom to which they are attached form a 3-7 membered ring, optionally     containing one or more for heteroatoms selected from O, NH and S,     and wherein said ring is optionally substituted with one or more     R^(a);

-   R³, R⁴ and R⁵ are independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, phenyl and     cyclopropyl, wherein said C₁₋₆ alkyl, phenyl and cyclopropyl are     optionally substituted by one or more R^(a);

-   or a pharmaceutically acceptable salt or solvate thereof.

95. A method according to paragraph 94 wherein the microbial infection is a bacterial infection.

96. A method according to paragraph 95 wherein the bacterial infection is Wolbachia infection.

97. A compound for use according to paragraphs 81 to 88 or a method according to paragraphs 89 to 96 wherein in the compound of Formula II, or a salt or solvate thereof,

-   A represents a fused aromatic ring selected from,

-   

-   

-   X¹, X² and X³ are independently selected from N and CH;

-   Q is a group selected from an C₃₋₁₁cycloalkyl optionally substituted     by 1-21 R^(b), 3-15 membered heterocycloalkyl optionally substituted     by 1-28 R^(b), C₆₋₁₁ aryl group optionally substituted with by 1-11     R^(b), 5-15 membered heteroaryl optionally substituted by 1-15     R^(b);

-   R⁶ is selected from hydrogen and C₁₋₆ alkyl;

-   R⁷ and R⁷′ are independently selected from hydrogen, C₃₋₆     cycloalkyl, C₁₋₆ alkyl, where said C₃₋₆ cycloalkyl and C₁₋₆ alkyl     are optionally substituted by one or more R^(a); or

-   R⁷ and R⁷′, together with the carbon to which they are attached form     a 3-7 membered cycloalkyl ring, optionally substituted with one or     more R^(a), or R⁷ and R⁷′, together with the carbon to which they     are attached form a carbonyl group; or

-   R⁶ and R⁷, together with the atoms to which they are attached form a     3-7 membered heterocyclic ring, optionally substituted with one or     more R^(a);

-   n is a number selected from 1, 2 and 3;

-   R² is selected from —CN, —C(═O)R^(d), —C(═O)OR^(d),     —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d),     -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)R^(d),     —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d),     —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d) —OC(═O)R^(d),     —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)R^(d), —S(═O)₂R^(d),     —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d),     —OS(═O)₂NR^(c)R^(d), —S(═O)₂NR^(c)R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl     optionally substituted by 1-13 R^(e), C₂₋ ₆alkenyl optionally     substituted by 1-11 R^(e), C₂₋₆alkynyl optionally substituted by 1-9     R^(e), C₆₋₁₁aryl optionally substituted by 1-11 R^(e),     (C₇₋₁₆)alkylaryl optionally substituted by 1-9 R^(e), C₃₋     ₁₁cycloalkyl optionally substituted by 1-21 R^(e),     (C₄₋₁₇)cycloalkylalkyl optionally substituted by 1-32 R^(e), 3-15     membered heterocycloalkyl optionally substituted by 1-28 R^(e), 4-21     membered alkylheterocycloalkyl optionally substituted by 1-40 R^(e),     5-15 membered heteroaryl optionally substituted by 1-15 R^(e), and     6-21 membered alkylheteroaryl optionally substituted by 1-27 R^(e);     each R^(a) is independently selected from hydroxyl, halogen, CN,     C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7     membered heterocycloalkyl, wherein said C₃₋₆ cycloalkyl and 3-7     membered heterocycloalkyl are optionally substituted with one or     more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl,     C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋ ₆ alkyl;

-   each R^(b) and R^(e) is independently selected from hydroxyl, =O,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, O-C₁₋₆     alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, —C(═O)R^(d),     —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d),     —NR^(c)C(═O)R^(d), —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d),     —NR^(c)S(═O)₂R^(d), —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d),     —OC(═O)R^(d), —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)₂R^(d),     —S(═O)R^(d), —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d),     —S(═O)NR^(c)R^(d), —OS(═O)₂NR^(c)R^(d), and —S(═O)₂NR^(c)R^(d),     where said C₃₋₆ cycloalkyl, C₁₋₆ alkyl, and 3-7 membered     heterocycloalkyl are optionally substituted with one or more groups     selected from hydroxyl, halogen, =O, CN, C₁₋₆ haloalkyl, C₁₋₆     haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl;

-   each R^(c) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆     alkyl;

-   each R^(d) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, 3-7 membered heterocycloalkyl, C₃₋₆     cycloalkyl, C₁₋₆ alkyl, O-C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said     C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆     cycloalkyl are optionally substituted with one or more groups     selected from hydroxyl, halogen, CN, amino, C₁₋₆ haloalkyl, C₃₋₆     cycloalkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl, C₁₋₆ alkyl     and O-C₁₋₆ alkyl; or

-   R^(c) and R^(d), when attached to the same atom, together with the     atom to which they are attached form a 3-7 membered ring, optionally     containing one or more for heteroatoms selected from O, NH and S,     and wherein said ring is optionally substituted with one or more     R^(a);

-   R³, R⁴ and R⁵ are independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, phenyl and     cyclopropyl, wherein said C₁₋₆ alkyl, phenyl and cyclopropyl are     optionally substituted by one or more R^(a);

-   with the provisos that:     -   (i) when X¹ is N, X² and X³ cannot both be CH;     -   (ii) when Q is phenyl, R^(b) is not such that Q is a         3,4-di-O-C₁₋₆ alkyl phenyl, a 3,5-di-O-C₁₋₆ alkyl phenyl or a         3,4,5-tri-O-C₁₋₆ alkyl phenyl; and     -   (iii) the compound of Formula (I) is not         -   N-(4-fluorobenzyl)-2-(piperidinyl-1-yl)pyrido[2,3-d]pyrimidin-4-amine,         -   N-(4-fluorobenzyl)-2-(piperidinyl-1-yl)pyrido[3,2-d]pyrimidin-4-amine,         -   N-(4-fluorobenzyl)-2-(piperidinyl-1-yl)thieno[3,2-d]pyrimidin-4-amine.

98. A compound for use or a method according to any one of paragraphs 81 to 97 wherein A is,

99. A compound for use or a method according to any one of paragraphs 81 to 98, wherein X¹ is N.

100. A compound for use or a method according to any one of paragraphs 81 to 99, wherein one of X² and X³ is N and the other is CH.

101. A compound for use or a method according to any one of paragraphs 81 to 100, wherein X² is CH and X³ is N.

102. A compound for use or a method according to any one of paragraphs 81 to 101, wherein X¹ is N and A is selected from

103. A compound for use or a method according to any one of paragraphs 81 to 97, wherein A is

104. A compound for use or a method according to any one of paragraphs 81 to 103, wherein Q is a group selected from a 3-15 membered heterocycloalkyl optionally substituted by one or more R^(b), C₆₋₁₁ aryl group optionally substituted with by one or more R^(b), and a 5-15 membered heteroaryl optionally substituted by one or more R^(b).

105. A compound for use or a method according to any one of paragraphs 81 to 104, wherein Q is a group selected from a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(b), C₆₋₁₁ aryl group optionally substituted with by 1-11 R^(b), and a 5-15 membered heteroaryl optionally substituted by 1-15 R^(b).

106. A compound for use or a method according to any one of paragraphs 81 to 105, wherein Q is a group selected from a C₆₋₁₁ aryl group optionally substituted with by 1-11 R^(b) and a 5-15 membered heteroaryl optionally substituted by 1-15 R^(b).

107. A compound for use or a method according to any one of paragraphs 81 to 106, wherein Q is a group selected from a C₆ aryl group optionally substituted with by one or more R^(b) and a 5-6 membered heteroaryl optionally substituted by one or more R^(b).

108. A compound for use or a method according to any one of paragraphs 81 to 107, wherein Q is selected from a phenyl or pyridyl group optionally substituted with 1-5 R^(b).

109. A compound for use or a method according to any one of paragraphs 81 to 108, wherein Q is a group of Formula III (wherein the dotted line indicates the point of attachment):

wherein

-   X⁴ is selected from CH and N; -   m is selected from 0, 1 and 2; and -   R^(b) is as previously defined.

110. A compound for use or a method according to any one of paragraphs 81 to 109, wherein Q is a group of Formula Illa:

wherein

-   X⁴ is selected from CH and N; and -   R^(b) is as previously defined.

111. A compound for use or a method according to any one of paragraphs 81 to 110, wherein each R^(b) is independently selected from hydroxyl, =O, halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆ alkyl, O-C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, —NR^(c)R^(d), —NR^(c)C(═O)R^(d), —OR^(d), —SR^(d), —S(═O)₂R^(d), —S(═O)R^(d), —S(═O)NR^(c)R^(d), and —S(═O)₂NR^(c)R^(d), where said C₃₋₆ cycloalkyl, C₁₋₆alkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

112. A compound for use or a method according to any one of paragraphs 81 to 111, wherein each R^(b) is independently selected from hydroxyl, =O, halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, O-C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, —NR^(c)R^(d), and —S(═O)₂R^(d), where said C₃₋₆ cycloalkyl, C₁₋₆ alkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

113. A compound for use or a method according to any one of paragraphs 81 to 112, wherein each R^(b) is independently selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

114. A compound for use or a method according to any one of paragraphs 81 to 113, wherein each R^(b) is independently selected from fluoro, chloro, and CF₃.

115. A compound for use or a method according to any one of paragraphs 81 to 114, wherein Q is selected from:

116. A compound for use or a method according to any one of paragraphs 81 to 115, wherein R⁶ is selected from hydrogen, methyl and ethyl.

117. A compound for use or a method according to any one of paragraphs 81 to 116, wherein R⁶ is selected from hydrogen and methyl.

118. A compound for use or a method according to any one of paragraphs 81 to 117, wherein R⁷ and R⁷′ are independently selected from hydrogen, methyl and cyclopropyl.

119. A compound for use or a method according to any one of paragraphs 81 to 118, wherein R⁷ and R⁷′ are independently selected from hydrogen and methyl.

120. A compound for use or a method according to any one of paragraphs 81 to 119, wherein R⁷′ is hydrogen.

121. A compound for use or a method according to any one of paragraphs 81 to 117, wherein R⁷ and R⁷′, together with the atom to which they are attached form a C₃₋₇ cycloalkyl ring, optionally substituted by one or more R^(a).

122. A compound for use or a method according to any one of paragraphs 81 to 117, wherein R⁷ and R⁷′, together with the atom to which they are attached form a cyclopropyl ring, optionally substituted by one or more R^(a).

123. A compound for use or a method according to any one of paragraphs 81 to 120, wherein R⁶ and R⁷′ are both hydrogen.

124. A compound for use or a method according to any one of paragraphs 81 to 120, wherein R⁶, R⁷ and R⁷′ are each hydrogen.

125. A compound for use or a method according to any one of paragraphs 81 to 115, wherein R⁶ and R⁷ together with the atoms to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl ring.

126. A compound for use or a method according to any one of paragraphs 81 to 125, wherein n is 1 or 2.

127. A compound for use or a method according to any one of paragraphs 81 to 126, wherein n is 1.

128. A compound for use or a method according to any one of paragraphs 81 to 127, wherein R² is selected from —CN, —C(═O)R^(d), —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d), -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)R^(d), —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d), —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d) —OC(═O)R^(d), —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)R^(d), —S(═O)₂R^(d), —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d), —OS(═O)₂NR^(c)R^(d), —S(═O)₂NR^(c)R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl optionally substituted by 1-13 R^(e), C₂₋ ₆alkenyl optionally substituted by 1-11 R^(e), C₂₋₆alkynyl optionally substituted by 1-9 R^(e), C₆₋₁₁aryl optionally substituted by 1-11 R^(e), (C₇₋₁₆)alkylaryl optionally substituted by 1-9 R^(e), C₃₋ ₁₁cycloalkyl optionally substituted by 1-21 R^(e), (C₄₋₁₇)cycloalkylalkyl optionally substituted by 1-32 R^(e), 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e), 4-21 membered alkylheterocycloalkyl optionally substituted by 1-40 R^(e), 5-15 membered heteroaryl optionally substituted by 1-15 R^(e), and 6-21 membered alkylheteroaryl optionally substituted by 1-27 R^(e);

129. A compound for use or a method according to any one of paragraphs 81 to 128, wherein R² is selected from —CN, —C(═O)R^(d), —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d), -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)R^(d), —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d), —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d) —OC(═O)R^(d), —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)R^(d), —S(═O)₂R^(d), —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d), —OS(═O)₂NR^(c)R^(d), —S(═O)₂NR^(c)R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl optionally substituted by 1-13 R^(e), C₂₋ ₆alkenyl optionally substituted by 1-11 R^(e), C₂₋₆alkynyl optionally substituted by 1-9 R^(e), C₆₋₁₁aryl optionally substituted by 1-11 R^(e), (C₇₋₁₆)alkylaryl optionally substituted by 1-9 R^(e), C₃₋ ₁₁cycloalkyl optionally substituted by 1-21 R^(e), (C₄₋₁₇)cycloalkylalkyl optionally substituted by 1-32 R^(e), 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e), 4-21 membered alkylheterocycloalkyl optionally substituted by 1-40 R^(e), 5-15 membered heteroaryl optionally substituted by 1-15 R^(e), and 6-21 membered alkylheteroaryl optionally substituted by 1-27 R^(e);

130. A compound for use or a method according to any one of paragraphs 81 to 129, wherein R² is selected from —CN, —C(═O)R^(d), —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —NR^(c)R^(d), -NR^(c)(C₁₋ ₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)R^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d), —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d) —OC(═O)R^(d), —S(═O)R^(d), —S(═O)₂R^(d), —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d), —OS(═O)₂NR^(c)R^(d), —S(═O)₂NR^(c)R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl optionally substituted by 1-13 R^(e), C₆₋₁₁aryl optionally substituted by 1-11 R^(e), C₃₋₁₁cycloalkyl optionally substituted by 1-21 R^(e), 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e), and 5-15 membered heteroaryl optionally substituted by 1-15 R^(e).

131. A compound for use or a method according to any one of paragraphs 81 to 130, wherein R² is selected from —CN, —C(═O)R^(d), C(═O)NR^(c)R^(d), —NR^(c)R^(d), -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)NR^(c)R^(d), —OR^(d), —SR^(d), —S(═O)₂R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl optionally substituted by 1-13 R^(e), C₆₋₁₁aryl optionally substituted by 1-11 R^(e), C₃₋₁₁cycloalkyl optionally substituted by 1-21 R^(e), 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e), and 5-15 membered heteroaryl optionally substituted by 1-15 R^(e).

132. A compound for use or a method according to any one of paragraphs 81 to 131, wherein R² is selected from NR^(c)R^(d), -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)NR^(c)R^(d), —OR^(d), —SR^(d), C₁₋ ₁₀ haloalkyl, C₁₋₁₀alkyl optionally substituted by 1-13 R^(e), C₆₋₁₁aryl optionally substituted by 1-11 R^(e), C₃₋₁₁cycloalkyl optionally substituted by 1-21 R^(e), 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e), and 5-15 membered heteroaryl optionally substituted by 1-15 R^(e).

133. A compound for use or a method according to any one of paragraphs 81 to 132, wherein R² is selected from NR^(c)R^(d), -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), C₁₋₁₀alkyl optionally substituted by 1-13 R^(e), C₆₋₁₁aryl optionally substituted by 1-11 R^(e), C₃₋₁₁cycloalkyl optionally substituted by 1-21 R^(e), 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e), and 5-15 membered heteroaryl optionally substituted by 1-15 R^(e).

134. A compound for use or a method according to any one of paragraphs 81 to 133, wherein R² is selected from NR^(c)R^(d), -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), C₁₋₁₀alkyl optionally substituted by 1-13 R^(e), and 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e). Suitably, R^(c) is C₁₋₆ alkyl, and R^(d) is independently selected from C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

135. A compound for use or a method according to any one of paragraphs 81 to 134, wherein R² is selected from NR^(c)R^(d) and a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e). Suitably, R^(c) is C₁₋₆ alkyl, and R^(d) is independently selected from C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

136. A compound for use or a method according to any one of paragraphs 81 to 135, wherein R² is selected from NR^(c)R^(d) and a 5-10 membered heterocycloalkyl optionally substituted by one or more R^(e). Suitably, R^(c) is C₁₋₆ alkyl, and R^(d) is independently selected from C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

137. A compound for use or a method according to any one of paragraphs 81 to 136, wherein R² is selected from NR^(c)R^(d) and a 5-7 membered heterocycloalkyl optionally substituted by one or more R^(e). Suitably, R^(c) is C₁₋₆ alkyl, and R^(d) is independently selected from C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

138. A compound for use or a method according to any one of paragraphs 81 to 137, wherein R² is selected from NR^(c)R^(d), azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, wherein said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl are optionally substituted by one or more R^(e). Suitably, R^(c) is C₁₋₆ alkyl, and R^(d) is independently selected from C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

139. A compound for use or a method according to any one of paragraphs 81 to 138, wherein R² is selected from NR^(c)R^(d); and

each of which may optionally be substituted with one or more R^(e). Suitably, R^(c) is C₁₋₆ alkyl, and R^(d) is independently selected from C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

140. A compound according to any one of paragraphs 81 to 139, or a salt or solvate thereof, wherein R² is selected from

each of which may optionally be substituted with one or more R^(e).

141. A compound according to any one of paragraphs 81 to 140, or a salt or solvate thereof, wherein R² is selected from

142. A compound for use or a method according to any one of paragraphs 81 to 141, wherein R^(e) is independently selected from hydroxyl, =O, halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, O-C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, —NR^(c)R^(d), where said C₃₋₆ cycloalkyl, C₁₋₆ alkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

143. A compound for use or a method according to any one of paragraphs 81 to 142, wherein R^(e) is independently selected from hydroxyl, =O, halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

144. A compound for use or a method according to any one of paragraphs 81 to 143, wherein R^(e) is independently selected from halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

145. A compound for use or a method according to any one of paragraphs 81 to 144, wherein R^(e) is independently selected from halogen, CN, C₁₋₃ haloalkyl, C₁₋₃ haloalkoxy, C₁₋₃ alkyl and O-C₁₋₃ alkyl.

146. A compound for use or a method according to any one of paragraphs 81 to 145, wherein R^(e) is independently selected from fluoro, chloro, CN, CF₃, OCF₃ and C₁₋₃ alkyl.

147. A compound for use or a method according to any one of paragraphs 81 to 146, wherein each R^(e) is independently selected from fluoro, chloro, CN, CF₃, OCF₃, and methyl.

148. A compound for use or a method according any one of paragraphs 81 to 147, wherein each R^(c) is independently selected from hydrogen, hydroxyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl;

149. A compound for use or a method according to any one of paragraphs 81 to 148, wherein each R^(c) is independently selected from hydrogen and C₁₋₆ alkyl, suitably C₁₋₆ alkyl.

150. A compound for use or a method according to any one of paragraphs 81 to 149, wherein each R^(c) is independently selected from hydrogen and C₁₋₃ alkyl, suitably C₁₋₃ alkyl.

151. A compound for use or a method according to any one of paragraphs 81 to 150, wherein each R^(d) is independently selected from hydrogen, 3-7 membered heterocycloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

152. A compound for use or a method according to any one of paragraphs 81 to 151, wherein each R^(d) is independently selected from 3-7 membered heterocycloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

153. A compound for use or a method according to any one of paragraphs 81 to 152, wherein each R^(d) is independently selected from C₃₋₆cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

154. A compound for use or a method according to any one of paragraphs 81 to 153, wherein R^(c) and R^(d) are independently selected from C₁₋₆ alkyl.

155. A compound for use or a method according to any one of paragraphs 81 to 154, wherein R³, R⁴ and R⁵ are independently selected from hydrogen, halogen and C₁₋₆ alkyl.

156. A compound for use or a method according to any one of paragraphs 81 to 155, wherein R³ is H.

157. A compound for use or a method according to any one of paragraphs 81 to 156, wherein R⁴ is H.

158. A compound for use or a method according to any one of paragraphs 81 to 157, wherein R⁵ is H.

159. A compound for use or a method according to any one of paragraphs 81 to 159, wherein R⁴ and R⁵ are H.

160. A compound for use or a method according to any one of paragraphs 81 to 159, wherein R³, R⁴ and R⁵ are H.

161. A compound for use or a method according to any one of paragraphs 97, which is a sub-Formula IIa:

wherein,

-   R⁶ is selected from hydrogen and C₁₋₆ alkyl; -   R⁷ is selected from hydrogen, =O, C₃₋₆ cycloalkyl, C₁₋₆ alkyl, where     said C₃₋₆ cycloalkyl, C₁₋₆ alkyl are optionally substituted by one     or more R^(a); or -   R⁶ and R⁷, together with the atoms to which they are attached form a     3-7 membered heterocyclic ring, optionally substituted with one or     more R^(a); -   X⁴ is selected from CH and N; -   R² is selected from —CN, —C(═O)R^(d), —C(═O)OR^(d),     —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d),     -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)R^(d),     —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d),     —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d) —OC(═O)R^(d),     —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)R^(d), —S(═O)₂R^(d),     —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d),     —OS(═O)₂NR^(c)R^(d), —S(═O)₂NR^(c)R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl     optionally substituted by 1-13 R^(e), C₂₋ ₆alkenyl optionally     substituted by 1-11 R^(e), C₂₋₆alkynyl optionally substituted by 1-9     R^(e), C₆₋₁₁aryl optionally substituted by 1-11 R^(e),     (C₇₋₁₆)alkylaryl optionally substituted by 1-9 R^(e), C₃₋     ₁₁cycloalkyl optionally substituted by 1-21 R^(e),     (C₄₋₁₇)cycloalkylalkyl optionally substituted by 1-32 R^(e), 3-15     membered heterocycloalkyl optionally substituted by 1-28 R^(e), 4-21     membered alkylheterocycloalkyl optionally substituted by 1-40 R^(e),     5-15 membered heteroaryl optionally substituted by 1-15 R^(e), and     6-21 membered alkylheteroaryl optionally substituted by 1-27 R^(e); -   each R^(a) is independently selected from hydroxyl, halogen, CN,     C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7     membered heterocycloalkyl, wherein said C₃₋₆ cycloalkyl, 3-7     membered heterocycloalkyl are optionally substituted with one or     more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl,     C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl; -   each R^(b) and R^(e) is independently selected from hydroxyl, =O,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆     alkyl, O-C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl,     —C(═O)R^(d), —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d),     —NR^(c)R^(d), —NR^(c)C(═O)R^(d), —NR^(c)C(═O)OR^(d),     —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d),     —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d), —OC(═O)R^(d),     —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)₂R^(d), —S(═O)R^(d),     —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d),     —OS(═O)₂NR^(c)R^(d), and —S(═O)₂NR^(c)R^(d), where said C₃₋₆     cycloalkyl, C₁₋₆ alkyl, and 3-7 membered heterocycloalkyl are     optionally substituted with one or more groups selected from     hydroxyl, halogen, =O, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₆     cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl; -   each R^(c) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆     alkyl; -   each R^(d) is independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, 3-7 membered heterocycloalkyl, C₃₋₆     cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl, C₆₋₁₁ aryl, wherein said     C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆     cycloalkyl are optionally substituted with one or more groups     selected from hydroxyl, =O, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆     cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆alkyl; or -   R^(c) and R^(d), when attached to the same atom, together with the     atom to which they are attached form a 3-7 membered ring, optionally     substituted with one or more R^(a); and -   R⁴ and R⁵ are independently selected from hydrogen, hydroxyl,     halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, and C₁₋₆ alkyl,     optionally substituted by one or more R^(a).

162. A compound for use or a method according to paragraph 161, wherein R⁴ and R⁵ are hydrogen.

163. A compound for use or a method according to any one of paragraphs 161 to 162, wherein each R^(b) is independently selected from fluoro, chloro, and CF₃.

164. A compound for use or a method according to any one of paragraphs 161 to 163, wherein R⁶ and R⁷ are both hydrogen.

165. A compound for use or a method according to any one of paragraphs 161 to 164, wherein R² is selected from —CN, —C(═O)R^(d), —C(═O)NR^(c)R^(d), —NR^(c)R^(d), -NR^(c)(C₁₋₆alkyl)NR^(c)R^(d), —NR^(c)C(═O)NR^(c)R^(d), —OR^(d), —SR^(d), —S(═O)₂R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl optionally substituted by 1-13 R^(e), C₆₋₁₁aryl optionally substituted by 1-11 R^(e), C₃₋₁₁cycloalkyl optionally substituted by 1-21 R^(e), 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e), and 5-15 membered heteroaryl optionally substituted by 1-15 R^(e). Suitably, R^(c) is C₁₋₆ alkyl, and R^(d) is independently selected from C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

166. A compound for use or a method according to any one of paragraphs 161 to 165, wherein R² is selected from NR^(c)R^(d), C₁₋₁₀alkyl optionally substituted by 1-13 R^(e), and 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e). Suitably, R^(c) is C₁₋₆ alkyl, and R^(d) is independently selected from C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

167. A compound for use or a method according to any one of paragraphs 161 to 166, wherein R² is selected from NR^(c)R^(d); and

each of which may optionally be substituted with one or more R^(e). Suitably, R^(c) is C₁₋₆ alkyl, and R^(d) is independently selected from C₃₋₆ cycloalkyl, C₁₋₆ alkyl and C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl.

168. A compound according to any one of paragraphs 161 to 167, or a salt or solvate thereof, wherein R² is selected from

each of which may optionally be substituted with one or more R^(e).

169. A compound according to any one of paragraphs 161 to 168, or a salt or solvate thereof, wherein R² is selected from

170. A compound for use or a method according to any one of paragraphs 161 to 169, wherein each R^(e) is independently selected from fluoro, chloro, CN, CF₃, OCF₃, and methyl.

171. A compound for use or a method according to any one of paragraphs 161 to 170, wherein R^(c) and R^(d) are independently selected from C₁₋₆ alkyl.

172. A compound for use or a method according to any one of paragraphs 161 to 171, wherein the compound is selected from:

-   (3R)-3-methyl-4-(4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)morpholine -   2-(3-(difluoromethyl)azetidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((2R,3R)-2,3-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-isopropylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   N-(2-(trifluoromethyl)benzyl)-2-(3-(trifluoromethyl)pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-cyclopropylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   1-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperidine-3-carbonitrile -   1-(4-((2-(trifluoromethyl)benzyl)amino)pyrido[2,3-d]pyrimidin-2-yl)azetidine-3-carbonitrile -   2-(4,4-dimethylpiperidin-1-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-fluoropyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   1-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperidine-4-carbonitrile -   2-(3-(trifluoromethyl)azetidin-1-yl)-4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidine -   3-methyl-4-(4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)morpholine -   (S)-2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-(trifluoromethyl)azetidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-chloropiperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-chloropiperidin-1-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   N²-isopropyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine     methanesulfonate -   2-(4,4-difluoropiperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-fluoropiperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3,3-difluoropyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine     methanesulfonate -   2-(3,3-difluoropyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine     methanesulfonate -   2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   N-isopropyl-4-(2-(2-(trifluoromethyl)phenyl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-amine -   N²-cyclopropyl-N²-methyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   2-(2,2-dimethylazetidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   N²-(tert-butyl)-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-isopropyl-N²,N⁴-dimethyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-cyclopropyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine     methanesulfonate -   N²-cyclopropyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-cyclopropyl-N⁴-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N,2-dimethyl-N-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidin-4-amine -   N-ethyl-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   N²-isopropyl-N4-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidine-2,4-diamine -   2-chloro-N-methyl-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine -   N²-isopropyl-N⁴-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidine-2,4-diamine     methanesulfonate -   N²-isopropyl-N⁴-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-isopropyl-N²-methyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine -   N²-isopropyl-N²-methyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine     methanesulfonate -   N⁴-(2-fluoro-6-(trifluoromethyl)benzyl)-N²-isopropylpyrido[2,3-d]pyrimidine-2,4-diamine -   2-(2-methylazetidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(pyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   N-isopropyl-N-methyl-4-(2-(2-(trifluoromethyl)phenyl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-amine -   2-(4,4-difluoropiperidin-1-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   3-methyl-4-(4-(2-(2-(trifluoromethyl)phenyl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)morpholine -   2-(4,4-difluoropiperidin-1-yl)-4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidine -   2-(3,3-difluoropyrrolidin-1-yl)-4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidine -   2-(4-(trifluoromethyl)piperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyr-imidin-4-amine -   2-(2,2-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3,3-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-methylmorpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   4-methyl-1-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperidine-4-carbonitrile -   2-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine     methanesulfonate -   2-(2-(trifluoromethyl)piperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   1-(4-((2-(trifluoromethyl)benzyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperidine-3-carbonitrile -   2-((2S,5R)-2,5-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(6-oxa-9-azaspiro[4.5]decan-9-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((3R)-3,5-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-cyclopropylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((2S,5S)-2,5-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   (R)-2-(3-(difluoromethoxy)pyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   (S)-2-(3-(difluoromethoxy)pyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-(difluoromethyl)morpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   4-(4-((2-(trifluoromethyl)benzyl)amino)pyrido[2,3-d]pyrimidin-2-yl)morpholine-2-carbonitrile -   2-((2R,3S)-2,3-dimethylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   (3S)-3-methyl-4-(4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)morpholine -   (3R)-3-methyl-4-(4-(2-(2-(trifluoromethyl)phenyl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)morpholine -   (3S)-3-methyl-4-(4-(2-(2-(trifluoromethyl)phenyl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2-yl)morpholine -   2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   (S)-2-(3-methylmorpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   (S)-2-(3-methylmorpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine     methanesulfonate -   2-(4-chloropiperidin-1-yl)-4-(2-(2-(trifluoromethyl)pyridin-3-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidine -   N-((2-(trifluoromethyl)pyridin-3-yl)methyl)-2-(3-(trifluoromethyl)pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2,2-dimethylmorpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-oxa-7-azaspiro[2.5]octan-7-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-(fluoromethyl)piperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyri-midin-4-amine -   (2-(trifluoromethyl)pyridin-3-yl)metha     4-methyl-1-(4-((2-(trifluoromethyl)benzyl)amino)pyrido[2,3-d]pyrimidin-2-yl)piperidine-4-carbonitrile -   N-((2-(trifluoromethyl)pyridin-3-yl)methyl)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-chloropyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(2-(trifluoromethyl)benzyl)     pyrido[2,3-d]pyrimidin-4-amine -   2-(4-(trifluoromethoxy)piperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-(trifluoromethoxy)piperidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine     methanesulfonate -   2-(3-(difluoromethyl)azetidin-1-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-(difluoromethyl)morpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(4-azaspiro[2.5]octan-4-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(3-(trifluoromethoxy)pyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(5-azaspiro[3.4]octan-5-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(2-((trifluoromethoxy)methyl)pyrrolidin-1-yl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine -   2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine -   2-((3R)-3,5-dimethylmorpholino)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine.

173. A compound for use according to any one of paragraphs 81 to 88 when X¹, X² and X³ are CH, R⁴ is not Cl.

174. A method according to any one of paragraphs 89 to 96 wherein when X¹, X² and X³ are CH, R⁴ is not Cl.

Though the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.

Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein.

Salts and Solvates

The compounds (including final products and intermediates) described herein may be isolated and used per se or may be isolated in the form of a salt, suitably pharmaceutically acceptable salts. It should be understood that the terms “salt(s)” and “salt form(s)” used by themselves or in conjunction with another term or terms encompasses all inorganic and organic salts, including industrially acceptable salts, as defined herein, and pharmaceutically acceptable salts, as defined herein, unless otherwise specified. As used herein, industrially acceptable salts are salts that are generally suitable for manufacturing and/or processing (including purification) as well as for shipping and storage, but may not be salts that are typically administered for clinical or therapeutic use. Industrially acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more.

Pharmaceutically acceptable salts, as used herein, are salts that are generally chemically and/or physically compatible with the other ingredients comprising a formulation, and/or are generally physiologically compatible with the recipient thereof. Pharmaceutically acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more. It should be understood that pharmaceutically acceptable salts are not limited to salts that are typically administered or approved by the FDA or equivalent foreign regulatory body for clinical or therapeutic use in humans. A practitioner of ordinary skill will readily appreciate that some salts are both industrially acceptable as well as pharmaceutically acceptable salts. It should be understood that all such salts, including mixed salt forms, are within the scope of the application.

In one embodiment, the compounds of Formula I and II are isolated as pharmaceutically acceptable salts.

A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric or maleic acid. In addition a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

In general, salts of the present application can be prepared in situ during the isolation and/or purification of a compound (including intermediates), or by separately reacting the compound (or intermediate) with a suitable organic or inorganic acid or base (as appropriate) and isolating the salt thus formed. The degree of ionisation in the salt may vary from completely ionised to almost non-ionised. In practice, the various salts may be precipitated (with or without the addition of one or more co-solvents and/or anti-solvents) and collected by filtration or the salts may be recovered by evaporation of solvent(s). Salts of the present application may also be formed via a “salt switch” or ion exchange/double displacement reaction, i.e. reaction in which one ion is replaced (wholly or in part) with another ion having the same charge. One skilled in the art will appreciate that the salts may be prepared and/or isolated using a single method or a combination of methods.

Representative salts include, but are not limited to, acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate and the like. Other examples of representative salts include alkali or alkaline earth metal cations such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, lysine, arginine, benzathine, choline, tromethamine, diolamine, glycine, meglumine, olamine and the like.

Certain compounds of the Formula I may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess antiproliferative activity.

Polymorphs

It is also to be understood that certain compounds of the Formula I may exhibit polymorphism, and that the invention encompasses all such forms that possess antiproliferative activity.

N-oxides

Compounds of the Formula I containing an amine function may also form N-oxides. A reference herein to a compound of the Formula I that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4^(th) Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

Tautomers

Compounds of the Formula I may exist in a number of different tautomeric forms and references to compounds of the Formula I include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula I. Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), pyrimidone/hydroxypyrimidine, imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.

Isomers

Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

Certain compounds of Formula I may have one or more asymmetric centers and therefore can exist in a number of stereoisomeric configurations. Consequently, such compounds can be synthesized and/or isolated as mixtures of enantiomers and/or as individual (pure) enantiomers, and, in the case of two or more asymmetric centers, single diastereomers and/or mixtures of diastereomers. It should be understood that the present application includes all such enantiomers and diastereomers and mixtures thereof in all ratios.

Isotopes

The compounds of the present invention are described herein using structural formulas that do not specifically recite the mass numbers or the isotope ratios of the constituent atoms. As such it is intended that the present application includes compounds in which the constituent atoms are present in any ratio of isotope forms. For example, carbon atoms may be present in any ratio of ¹²C, ¹³C, and ¹⁴C; hydrogen atoms may be present in any ratio of ¹H, ²H, and ³H; etc. Preferably, the constituent atoms in the compounds of the present invention are present in their naturally occurring ratios of isotope forms.

Prodrugs and Metabolites

The compounds of Formula I may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention. A pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached. Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula I and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula I.

Accordingly, the present invention includes those compounds of the Formula I as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula I may be a synthetically-produced compound or a metabolically-produced compound.

A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.

Various forms of pro-drug have been described, for example in the following documents :

-   a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder,     et al. (Academic Press, 1985); -   b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); -   c) A Textbook of Drug Design and Development, edited by     Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and     Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); -   d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); -   e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285     (1988); -   f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); -   g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”,     A.C.S. Symposium Series, Volume 14; and -   h) E. Roche (editor), “Bioreversible Carriers in Drug Design”,     Pergamon Press, 1987.

A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I that possesses a carboxy group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of the Formula I containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxy include C₁₋₆alkyl esters such as methyl, ethyl and tert-butyl, C₁₋₆alkoxymethyl esters such as methoxymethyl esters, C₁₋₆alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, C₃₋₈cycloalkylcarbonyloxy- C₁₋₆alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and C₁₋₆alkoxycarbonyloxy- C₁₋₆alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters.

A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the Formula I containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C₁₋₁₀alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C₁₋₁₀alkoxycarbonyl groups such as ethoxycarbonyl, N,N -(C₁₋₆)₂carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C₁₋₄alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C₁₋₄alkylamine such as methylamine, a (C₁₋₄alkyl)₂amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C₁₋ ₄alkoxy- C₂₋₄alkylamine such as 2-methoxyethylamine, a phenyl-C₁₋₄alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C₁₋₁₀alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C₁₋₄alkyl)piperazin-1-ylmethyl.

The in vivo effects of a compound of the Formula I may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula I. As stated hereinbefore, the in vivo effects of a compound of the Formula I may also be exerted by way of metabolism of a precursor compound (a pro-drug).

Pharmaceutical Compositions

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.

An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.

The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.

It is to be noted that dosages and dosing regimens may vary with the type and severity of the condition to be alleviated, and may include the administration of single or multiple doses, i.e. QD (once daily), BID (twice daily), etc., over a particular period of time (days or hours). It is to be further understood that for any particular subject or patient, specific dosage regimens may need to be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the pharmaceutical compositions. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the present application encompasses intra-patient dose-escalation as determined by the person skilled in the art. Procedures and processes for determining the appropriate dosage(s) and dosing regimen(s) are well-known in the relevant art and would readily be ascertained by the skilled artisan. As such, one of ordinary skill would readily appreciate and recognize that the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the pharmaceutical compositions described herein.

In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.

Therapeutic Uses and Applications

In another aspect, the present invention provides a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.

In another aspect, the present invention provides a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a filarial worm infection.

In another aspect, the present invention provides a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a disease or condition mediated by a filarial worm infection.

In another aspect, the present invention provides a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a microbial infection.

In one embodiment, the present invention provides a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of filariasis, suitably lymphatic filariasis, or onchocerciasis.

In another aspect, the present invention provides the use of a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a filarial worm infection.

In another aspect, the present invention provides the use of a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition mediated by a filarial worm infection.

In another aspect, the present invention provides the use of a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a microbial infection.

In another aspect, the present invention provides a method of treating or preventing a filarial worm infection, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method of treating or preventing a disease mediated by a filarial worm infection, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method of treating a microbial infection, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or II as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

In each of the above aspects or embodiments, the subject or patient treated is suitably a carrier of a filarial worm infection. In each of the above aspects or embodiments, the subject or patient treated is suitably a human.

In another aspect, the present invention provides a combination comprising a compound of Formula I or II, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, with one or more additional therapeutic agents.

In each of the above aspects, in one embodiment, the infection is with one or more filarial worms selected from Wuchereria bancrofti, Brugia malayi, Brugia timori and Onchocerca volvulus.

In each of the above aspects, in another embodiment, the infection is with one or more filarial worms selected from Wuchereria bancrofti, Brugia malayi and Brugia timori.

In each of the above aspects, in another embodiment, the infection is with one or more filarial worms selected from Onchocerca volvulus.

In each of the above aspects, in one embodiment, the disease or condition is mediated by a filarial worm infection with one or more filarial worms selected from Wuchereria bancrofti, Brugia malayi, Brugia timori and Onchocerca volvulus.

In each of the above aspects, in another embodiment, the disease or condition is mediated by a filarial worm infection with one or more filarial worms selected from Wuchereria bancrofti, Brugia malayi and Brugia timori.

In each of the above aspects, in another embodiment, the disease or condition is mediated by a filarial worm infection with one or more filarial worms selected from Onchocerca volvulus.

In each of the above aspects, in another embodiment, the disease or condition is filariasis, suitably lymphatic filariasis.

In each of the above aspects, in another embodiment, the disease or condition is selected from onchocerciasis or lymphatic filariasis.

In each of the above aspects, in one embodiment, the microbial infection is a bacterial infection.

In each of the above aspects, in another embodiment, the microbial infection is Wolbachia infection.

Routes of Administration

The compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e., at the site of desired action).

Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

EXAMPLES Chemistry

The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.

The compounds of the invention may be prepared using synthetic techniques that are known in the art (as illustrated by the examples herein).

Several methods for the chemical synthesis of the compounds of the present application are described herein. These and/or other well-known methods may be modified and/or adapted in various ways in order to facilitate the synthesis of additional compounds within the scope of the present application and claims. Such alternative methods and modifications should be understood as being within the spirit and scope of this application and claims. Accordingly, it should be understood that the methods set forth in the following descriptions, schemes and examples are intended for illustrative purposes and are not to be construed as limiting the scope of the disclosure.

Synthesis and Characterisation

¹H Nuclear Magnetic Resonance spectra were recorded on Bruker (300, 400 or 500 MHz) NMR spectrometers. Data analysis are reported as follows: chemical shift relative to TMS (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet), coupling constant (J, Hz), integration.

High resolution mass spectrometry (HRMS) was recorded on a VG analytical 7070E machine and Fisons TRIO spectrometers using electron ionisation (EI) and chemical ionisation (CI). LCMS was performed and recorded on Agilent 1200\G6110A or 1100\G1956A (LC) and SHIMADZU LCMS-2020 (MS) using electron spread ionisation (ESI). Data was reported as follows: (ionization method) main peak shift.

General Synthetic Route 1 (Route 1)

Example 1 Preparation of 2-chloro-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine

To a suspension of 2,4-dichlorothieno[3,2-d]pyrimidine (205 mg, 1.0 mmol) in THF (5 ml), 2-(trifluoromethyl)-benzylamine (214 mg, 0.17 ml, 1.2 mmol, 1.2eq) and triethylamine (0.28 ml, 2.0 mmol, 2.0eq) were added. The resulting mixture was heated to 65° C. for 3 hours. After cooled down to room temperature, ice-water (50 ml) was added to the reaction mixture, and the resulting mixture was kept stirring for 5~10 min. The precipitation was collected by filtration, washed with water and redissolved with EtOAc. The solution was dried with MgSO₄, and concentrated under vacuum to give the product 2-chloro-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine (330 mg, >95%) as a pale yellow solid. The product was used directly in the next step without any further purification.

Preparation of N²-isopropyl-N⁴-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidine-2,4-diamine

To the suspension of 2-chloro-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine (330 mg) in 1,4-dioxane (5 ml), isopropylamine (0.60 g, 0.87 ml, 10 mmol, 10eq.) was heated to 120° C. in seal-tube for 48 hours. After that, 1,4-dioxane and the excess isopropylamine was removed under vacuum. The residue was purified by flash column chromatograph eluting with 5~10% MeOH in DCM to give the product N²-isopropyl-N⁴-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidine-2,4-diamine (175 mg, 48%) as an off-white solid.

General Synthetic Route 2 (Route 2)

Example 2 Preparation of 2-methyl-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine

To a suspension of 4-chloro-2-methylthieno[3,2-d]pyrimidine (185 mg, 1.0 mmol) in THF (5 ml), 2-(trifluoromethyl)-benzylamine (214 mg, 0.17 ml, 1.2 mmol, 1.2eq) and triethylamine (0.28 ml, 2.0 mmol, 2.0eq) were added. The resulting mixture was heated to 75° C. for 36 hours. After cooled down to room temperature, ice-water (50 ml) was added to the reaction mixture, and the resulting mixture was kept stirring for 5~10 min. The precipitation was collected by filtration, washed with water and redissolved with EtOAc. The solution was dried with MgSO₄, and concentrated under vacuum to give the crude product. The crude was further purified by flash column chromatograph to give the product 2-methyl-N-(2-(trifluoromethyl)benzyl)thieno[3,2-d]pyrimidin-4-amine (150 mg, 46%) as a pale yellow solid.

General Synthetic Route 3 (Route 3)

Example 3 Preparation of 4-chloro-6-iodothieno[3,2-d]pyrimidine

The reaction was performed in anhydrous conditions and under nitrogen. 4-chlorothieno[3,2-d]pyrimidine (5 mmol, 850 mg) was dissolved in anhydrous THF (25 ml) in a 100 ml round bottomed flask. The mixture was cooled with dry-ice/acetone bath for 10 minutes. LDA 2 M (1.2 eq, 6 mmol, in THF) was added drop-wise to the mixture. The mixture was left to react for half an hour. I₂ (1.3 eq, 6.5 mmol) was dissolved in anhydrous THF (10 ml) and the mixture was slowly added to the reaction. After an hour the cold bath was removed and the mixture was left to stir for 2 more hours. Work up: H₂O (2 ml) was added to quench the reaction. The solvent was removed to dryness. H₂O (100 ml) was added to the residue and the mixture was stirred for 30 minutes. The precipitate was collected through filtration. The solid was washed with a Na₂S₂O₃ solution to remove the excess I₂. Purification: the product was dissolved in DCM and purified by silica fltration (5% EtOAc in DCM, 10% EtOAc in DCM). Product: 4-chloro-6-iodothieno[3,2-d]pyrimidine, 0.85 g, yield=57%, white solid. ¹H NMR (400 MHz, DMSO) δ 8.97 (s, 1H), 8.14 (s, 1H).

Preparation of 6-iodo-N-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidin-4-amine

The reaction was performed under nitrogen atmosphere. 4-chloro-6-iodothieno[3,2-d]pyrimidine (2.7 mmol, 800 mg), diisopropylethylamine (2 eq, 0.94 ml), αmethyl-2-trifluoromethylbenzylamine (1.2 eq, 620 mg) and 1-butanol (15 ml) were placed in asealed tube and heated to 110° C. overnight. The solvent was evaporated in vacuo. Purification: the product was purified by flash column chromatography (2% EtOAc in DCM). Product: 6-iodo-N-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidin-4-amine, 1.00 g, yield=81%, pale yellow solid. ¹H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.4 Hz, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 5.81 (p, J = 6.7 Hz, 1H), 4.95 (d, J = 5.9 Hz, 1H), 1.65 (d, J = 6.7 Hz, 3H).

Preparation of 6-phenyl-N-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidin-4-amine

The reaction was performed in anhydrous conditions and under nitrogen atmosphere. 6-iodo-N-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidin-4-amine (1 mmol, 450 mg), phenylboronic acid (1.5 eq, 180 mg), and K₃PO₄ (4 eq, 850 mg) were placed in a 50 ml flask. Anhydrous toluene (20 ml) was added. The reaction was degassed using a nitrogen-vacuum line and stirred. Pd(PPh₃)₄ (0.05eq, 60 mg) was added to the mixture. After completion the reaction was left to cool down at room temperature. Purification: the product was purified by silica filtration (50% EtOAc in Hexane) and then by flash column chromatography (30% EtOAc in Hexane). Product: 6-phenyl-N-(1-(2-(trifluoromethyl)phenyl)ethyl)thieno[3,2-d]pyrimidin-4-amine, 0.28 g, yield=70%, pale yellow solid.

General Synthetic Route 4 (Route 4)

Example 4 Preparation of 2-chloro-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)quinazolin-4-amine

A mixture of [2-(trifluoromethyl)-3-pyridyl]methanamine (176 mg, 1.00 mmol, 1.00 eq), 2,4-dichloroquinazoline (200 mg, 1.00 mmol, 1.00 eq) and Et₃N (202 mg, 2.00 mmol, 2.00 eq) in THF (10.00 mL) was stirred at 10-20° C. for 12 hours. LCMS showed all of 2,4-dichloroquinazoline was consumed and a new peak with desired MS. The mixture was concentrated to give a residue. The residue was triturated with EtOAc (2 mL). 2-chloro-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]quinazolin-4-amine (110 mg, 195 umol, 19% yield, 60% purity) was obtained as a light yellow solid.

Preparation of N²-isopropyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)quinazoline-2,4-diamine

A mixture of propan-2-amine (31 mg, 530 umol, 2.99 eq), 2-chloro-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]quinazolin-4-amine (100 mg, 177 umol, 1.00 eq) and TEA (54 mg, 531 umol, 3.00 eq) in DMSO (2.00 mL) was stirred at 110° C. for 12 hours. LCMS showed all of 2-chloro-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]quinazolin-4-amine was consumed and a new peak with desired MS. TLC (EtOAc/MeOH=15/1) showed all of 2-chloro-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]quinazolin-4-amine was consumed and a new spot. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL*3). The organic layer was dried over Na₂SO₄ and concentrated to give a residue. The residue was purified by prep-TLC (EtOAc/MeOH=15/1). N²-isopropyl-N⁴-[[2-(trifluoromethyl)-3-pyridyl]methyl]quinazoline-2,4-diamine (20 mg, 54 umol, 30% yield, 98% purity) was obtained as a light yellow solid.

General Synthetic Route 5 (Route 5)

Example 5 Preparation of N-(4-fluoro-2-(trifluoromethyl)benzyl)-2-methylquinazolin-4-amine

To a suspension of 4-chloro-2-methylquinazoline (188 mg, 1.0 mmol) in nBuOH (5 ml), 4-Fluoro-2-(trifluoromethyl)-benzylamine (239 mg, 1.2 mmol, 1.2eq) and diisopropylethylamine (0.35 ml, 2.0 mmol, 2.0eq) were added. The resulting mixture was heated to 120° C. for 12 hours. After cooled down to room temperature, ice-water (50 ml) was added to the reaction mixture, and the resulting mixture was kept stirring for 5~10 min. The precipitation was collected by filtration and dried to give the crude product. The crude was further purified by flash column chromatograph to give the product N-(4-fluoro-2-(trifluoromethyl)benzyl)-2-methylquinazolin-4-amine (170 mg, 50%) as an off-white solid.

General Synthetic Route 6 (Route 6)

Example 6 Preparation of 2-chloro-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine

To a mixture of [2-(trifluoromethyl)-3-pyridyl]methanamine (118.00 g, 549.34 mmol, 1.00 eq) and 2,4-dichloropyrido[2,3-d]pyrimidine (109.88 g, 549.34 mmol, 1.00 eq) in THF (200.00 mL) was added TEA (111.17 g, 1.10 mol, 152.29 mL, 2.00 eq) at 0° C. The mixture was stirred at 20° C. for 3 h. TLC (Ethyl acetate: Petroleum ether= 2: 1) showed a major new spot. The mixture was concentrated to remove half of solvent. The resultant mixture was diluted with H₂O (200 mL), then filtered to collected the yellow solid. The yellow solid was triturated from Ethyl acetate: Petroleum ether (2: 1, 30 mL) and dried under high vacuum to give 2-chloro-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrido[2,3-d]pyrimidin-4-amine (161.00 g, 469.21 mmol, 85% yield, 99% purity) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.62 (s, 1H), 9.02 (d, J=2.8 Hz, 1H), 8.78-8.80 (d, J=8.0 Hz, 1H), 8.65-8.66 (d, J=4.0 Hz, 1H), 8.04-8.06 (d, J=8.0 Hz, 1H), 7.61-7.70 (m, 2H), 4.94-4.95 (d, J=4.0 Hz, 1H).

Preparation of 2-(3-methylmorpholino)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine

To a mixture of 2-chloro-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrido[2,3-d]pyrimidin-4-amine (14.35 g, 42.24 mmol, 1.00 eq) and DIEA (10.92 g, 84.48 mmol, 14.76 mL, 2.00 eq) in DMSO (150.00 mL) was added 3-methylmorpholine (5.12 g, 50.68 mmol, 1.2 eq). The mixture was stirred at 90° C. for 16 h. LCMS showed a major peak with desired mass. The mixture was diluted with H₂O (300 mL) and the resulted mixture was stirred at 20° C. for 3 h. LCMS showed 88% of a major peak with desired mass. The mixture was filtered to collect the light yellow solid. The light yellow solid was trituration with Petroleum ether: Ethyl acetate (1:1, 50 mL), followed by filtration and the solid was dried under high vacuum to give crude product (16 g). Then the crude product was trituration with MeCN (120.00 mL) at 20° C. for 12 h. The mixture was filtered to collect the solid which was dried under high vacuum to give 2-(3-methylmorpholin-4-yl)-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrido[2,3-d]pyrimidin-4-amine (12.60 g, 30.78 mmol, 78% yield, 98.1% purity) as a light yellow solid.

General Synthetic Route 7 (Route 7)

Example 7 Preparation of 2-chloro-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[3,2-d]pyrimidin-4-amine

A mixture of [2-(trifluoromethyl)-3-pyridyl]methanamine (132 mg, 750 umol, 1.00 eq), 2,4-dichloropyrido[3,2-d]pyrimidine (150 mg, 750 umol, 1.00 eq) and Et₃N (152 mg, 1.50 mmol, 2.00 eq) in THF (10.00 mL) was stirred at 10-20° C. for 12 hours. LCMS showed all of 2,4-dichloropyrido[3,2-d]pyrimidine was consumed and a new peak with desired MS. The mixture was concentrated to give a residue. The residue was triturated with EtOAc (2 mL). 2-chloro-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrido[3,2-d]pyrimidin-4-amine (120 mg, 177 umol, 23% yield, 50% purity) was obtained as an off-white solid.

Preparation of N²-isopropyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[3,2-d]pyrimidine-2,4-diamine

A mixture of propan-2-amine (31 mg, 530 umol, 3.00 eq), 2-chloro-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrido[3,2-d]pyrimidin-4-amine (120 mg, 177 umol, 1.00 eq) and TEA (54 mg, 530 umol, 3.00 eq) in DMSO (2.00 mL) was stirred at 110° C. for 5 hours. LCMS showed all of 2-chloro-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrido[3,2-d]pyrimidin-4-amine was consumed and a new major peak with desired MS. 2 mL water was added to the mixture and filtered. The precipitate was washed with 0.5 mL EtOAc and dried. N²-isopropyl-N⁴-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrido[3,2-d]pyrimidine-2,4-diamine (44 mg, 122 umol, 68% yield, 99.2% purity) was obtained as a light yellow solid.

General Synthetic Route 8 (Route 8)

Example 8 Preparation of N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine

To a solution of 4-chloropyrido[2,3-d]pyrimidine (100 mg, 604 umol, 1.00 eq) and [2-(trifluoromethyl)-3-pyridyl]methanamine (160 mg, 906 umol, 1.50 eq) in THF (5.00 mL) was added TEA (122 mg, 1.21 mmol, 167 uL, 2.00 eq). The reaction mixture was stirred at 15° C. for 3 h. TLC (Dichloromethane: Methanol=10: 1) showed 4-chloropyrido[2,3-d]pyrimidine was consumed completely and a new spot was formed. The mixture was diluted with water (5 mL) and a lot of white solid was precipitated out. The mixture was filtered and the filter cake was washed with water (15 mL) and dried in vacuo to give N-[[2-(trifluoromethyl)-3-pyridyl] methyl]pyrido[2,3-d]pyrimidin-4-amine (36 mg, 117 umol, 19% yield, 100% purity) as a white solid.

General Synthetic Route 9 (Route 9)

Example 9 Preparation of 4-chloro-N-isopropyl-1,8-naphthyridin-2-amine

To a solution of 2,4-dichloro-1,8-naphthyridine (50 mg, 251 umol, 1 eq) and propan-2-amine (22 mg, 377 umol, 32 uL, 1.5 eq) in dioxane (6 mL) was added TEA (51 mg, 502 umol, 69 uL, 2 eq). The mixture was stirred at 90° C. for 16 hours. TLC (Petroleum ether: EtOAc=1: 1) showed that 2,4-dichloro-1,8-naphthyridine was consumed completely and several new spots. LCMS showed that a major peak of desired product’s MS was detected. The mixture was concentrated directly. The residue was purified by trituration from (H₂O: Petroleum ether: EtOAc=10: 10: 1) to obtain compound 4-chloro-N-isopropyl-1,8-naphthyridin-2-amine (35 mg, 158 umol, 63% yield) as a light brown solid. ¹H NMR (400 MHz, CDCl3-d) δ ppm 8.83 (dd, J=4.4, 1.6 Hz, 1H), 8.28 (dd, J=8.0, 1.9 Hz, 1H), 7.20 (dd, J=8.0, 4.5 Hz, 1H), 6.76 (s, 1H), 4.95 (br. s., 1H), 4.44 (d, J=5.6 Hz, 1H), 1.29 (d, J=6.5 Hz, 6H).

Preparation of N²-isopropyl-N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)-1,8-naphthyridine-2,4-diamine

A mixture of 4-chloro-N-isopropyl-1,8-naphthyridin-2-amine (150 mg, 676.6 umol, 1 eq) and [2-(trifluoromethyl)-3-pyridyl]methanamine (1.2 g, 6.8 mmol, 10 eq) was stirred at 180° C. for 0.5 hour under microwave and N₂. TLC (EtOAc) showed that 4-chloro-N-isopropyl-1,8-naphthyridin-2-amine was consumed completely and several new spots. LCMS showed that several peaks and 20% of desired product. To the mixture was added water (40 mL) and extracted with EtOAc (40 mL*2). The organic layers were washed with brine (40 mL), dried over Na₂SO₄ and concentrated. The residue was purified by prep-TLC (EtOAc). Then the crude product was further purified by prep-HPLC (Column: Phenomenex Synergi C18 150*30 mm*4 um; Condition: water(0.225%FA)-ACN). The salt product was basified by strong basic anion exchange resin. Then the residue was purified by prep-TLC (Dichloromethane: Methanol= 10: 1) to obtain N²-isopropyl-N⁴-[[2-(trifluoromethyl)-3-pyridyl]methyl]-1,8-naphthyridine-2,4-diamine (5.4 mg, 15 umol, 2% yield) as a light yellow solid.

General Synthetic Route 10 (Route 10)

Example 10 Preparation of N⁴-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-diamine

To a mixture of 2-chloro-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrido[2,3-d]pyrimidin-4-amine (50 mg, 147 umol, 1.00 eq) in DMSO (2.00 mL) was added NH₃·H₂O (10 mg, 294 umol, 11 uL, 2.00 eq). The mixture was stirred at 95° C. for 12 h. TLC (Ethyl acetate) showed most of 2-chloro-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrido[2,3-d]pyrimidin-4-amine was consumed and a major new spot. The mixture was diluted with water (10 mL). The precipitate was collected by filtration and purified by triturated from EtOAc (1 mL) to give N⁴-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrido[2,3-d]pyrimidine-2,4-diamine (20 mg, 62 umol, 42% yield) as a light yellow solid. ¹H NMR (300 MHz, DMSO-d6) δ ppm 8.62-8.67 (m, 3H), 8.40-8.43 (dd, J=6.0 Hz, J=3.0 Hz, 1H), 7.96-7.99 (d, J=9.0 Hz, 1H), 7.65-7.70 (dd, J=6.0 Hz, J=3.0 Hz, 1H), 7.05-7.09 (dd, J=6.0 Hz, J=3.0 Hz, 1H), 6.44 (bs, 2H), 4.90-4.92 (d, J=6.0 Hz, 2H).

Preparation of 1-(4-fluorophenyl)-3-(4-(((2-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrido[2,3-d]pyrimidin-2-yl)urea

A mixture of N⁴-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrido[2,3-d]pyrimidine-2,4-diamine (100 mg, 312 umol, 1.00 eq), 1-fluoro-4-isocyanato-benzene (128 mg, 937 umol, 105 uL, 3.00 eq) in dioxane (2.00 mL) was stirred at 120° C. under microwave for 30 min. TLC (Ethyl acetate: Petroleum ether=2: 1) showed most of N⁴-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrido[2,3-d]pyrimidine-2,4-diamine was consumed and two major new spots. The mixture was diluted with MeOH (5 mL). The precipitate was collected by filtration and purified by prep-HPLC (column: Phenomenex Synergi C18 150*30 mm*4 um;mobile phase: [water(0.225%FA)-ACN];B%: 30%-60%,12 min), then adjust the pH=7~8 with anion resin, followed by lyophilization to give 1-(4-fluorophenyl)-3-[4-[[2-(trifluoromethyl)phenyl]methylamino]pyrido[2,3-d]pyrimidin-2-yl]urea (10.6 mg, 23 umol, 7% yield) as a white solid.

General Synthetic Route 11 (Route 11)

Example 11 Preparation of Methyl 4-((2-(trifluoromethyl)benzyl)amino)pyrido[2,3-d]pyrimidine-2-carboxylate

The mixture of 2-chloro-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine (3.00 g, 8.96 mmol, 1.00 eq), Pd(dppf)Cl₂ (131 mg, 179 umol, 0.15 eq), TEA (2.92 g, 28.86 mmol, 4.00 mL, 3.22 eq) in MeOH (30 mL) was stirred at 80° C. under CO (45 psi) for 18 h. TLC (Ethyl acetate : Methanol= 20:1) showed most of the 2-chloro-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine was consumed and a new spot. The mixture was concentrated directly to remove the solvent. The residue was purified by chromatography (Ethyl acetate to Ethyl acetate: Methanol= 20:1) to get methyl 4-((2-(trifluoromethyl)benzyl)amino)pyrido[2,3-d]pyrimidine-2-carboxylate (2.20 g, 5.10 mmol, 57% yield, 84% purity) as a light yellow solid.

Preparation of (4-((2-(trifluoromethyl)benzyl)amino)pyrido[2,3-d]pyrimidin-2-yl)methanol

To a mixture of methyl 4-[[2-(trifluoromethyl)phenyl]methylamino]pyrido[2,3-d]pyrimidine-2-carboxylate (2.20 g, 6.07 mmol, 1.00 eq) in THF (30.00 mL) was added LiBH₄ (265 mg, 12.14 mmol, 2.00 eq) at 0° C. The mixture was stirred at 0° C. for 10 min. TLC (Ethyl acetate: Methanol= 10: 1) showed methyl 4-[[2-(trifluoromethyl)phenyl]methylamino]pyrido[2,3-d]pyrimidine-2-carboxylate was consumed completely and three new spots. The mixture was diluted with H₂O (100 mL), then the resultant mixture was extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (40 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by chromatography (Ethyl acetate: Methanol= 10: 1) to give (4-((2-(trifluoromethyl)benzyl)amino)pyrido[2,3-d]pyrimidin-2-yl)methanol (1.20 g, 2.58 mmol, 43% yield, 72% purity) as a yellow solid.

Preparation of 2-(chloromethyl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine

To a mixture of [4-[[2-(trifluoromethyl)phenyl]methylamino]pyrido[2,3-d]pyrimidin-2-yl]methanol (80 mg, 239 umol, 1.00 eq) and TEA (85 mg, 838 umol, 116 uL, 3.50 eq) in DCM (2.00 mL) was added MsCI (41 mg, 359 umol, 28 uL, 1.50 eq) at 0° C. Then the mixture was stirred at 20° C. for 12 h. TLC (EtOAc) showed little of [4-[[2-(trifluoromethyl)phenyl]methylamino]pyrido[2,3-d]pyrimidin-2-yl]methanol remained and a major new spot. The mixture was purified by prep-TLC (EtOAc) to give 2-(chloromethyl)-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine (30 mg, 83 umol, 34% yield, 97% purity) was obtained as a light yellow solid. ¹H NMR (400 MHz, DMSO-d6) δppm 9.25-9.27 (t, J=4.0 Hz, 1H), 9.03-9.04 (dd, J=4.0, 1.6 Hz, 1H), 8.79-8.82 (dd, J=8.0, 4.0 Hz, 1H), 7.75-7.77 (d, J=8.0 Hz, 1H), 7.57-7.64 (m, 3H), 7.47-7.51 (d, J=8.0 Hz, 1H), 4.99-5.00 (d, J=8.0 Hz, 1H), 4.58 (s, 2H).

Preparation of 2-((4-chloropiperidin-1-yl)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine

To a solution of 2-(chloromethyl)-N-[[2-(trifluoromethyl)phenyl]methyl]pyrido[2,3-d]pyrimidin-4-amine (85 mg, 241 umol, 1 eq) and 4-chloropiperidine (45 mg, 289 umol, 1.2 eq, HCl salt) in DMSO (2 mL) was added TEA (97 mg, 964 umol, 133 uL, 4 eq) . The mixture was stirred at 60° C. for 2 hour. LCMS showed the starting material was consumed completely and a major peak with desired product mass. The residue was purified by prep-HPLC (column: Gemini 150*25 5u;mobile phase: [water (0.05%ammonia hydroxide v/v)-ACN];B%: 36%-66%,12 min), followed by lyophilisation to give 2-((4-chloropiperidin-1-yl)methyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine (32.4 mg, 70 umol, 29% yield, 94.6% purity) as a light yellow solid.

The compounds of Table 1 were prepared using the general methodology outlined above:

TABLE 1 4 2-chloro-N-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-4-amine

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d₆) δ(ppm) 9.61 (t, J=5.33 Hz, 1H), 9.03 (dd, J=1.76, 4.39 Hz, 1H), 8.82 (dd, J=1.76, 8.28 Hz, 1H), 7.79 (d, J=7.53 Hz, 1H), 7.61-7.67 (m, 2H), 7.48-7.60 (m, 2H), 4.94 (d, J=5.27 Hz, 2H). LCMS (ES) C₁₅H₁₁N₄F3Cl [M+H]⁺ 339.1. 5 N²-isopropyl-N⁴-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidine-2,4-diamine

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 10.04 (br. s., 1H), 8.48-8.95 (m, 2H), 7.77 (d, J=7.78 Hz, 2H), 7.44-7.68 (m, 3H), 7.00-7.38 (m, 1H), 4.94 (d, J=4.89 Hz, 2H), 3.83-4.22 (m, 1H), 0.91-1.22 (m, 6H). LCMS (ES) C₁₈H₁₉N₅F3 [M+H]⁺ 362.2. 5_S N²-isopropyl-N⁴-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidine-2,4-diamine methanesulfonate

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 12.55 (br. s., 1H), 10.33 (br. s., 1H), 8.69-8.85 (m, 2H), 8.02 (d, J=7.4 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.46-7.67 (m, 4H), 4.99 (d, J=4.3 Hz, 2H), 3.96 (qd, J=6.5, 13.3 Hz, 1H), 2.37 (s, 3H), 0.96-1.22 (m, 6H). LCMS (ES) C₁₈H₁₉N₅F3 [M+H]⁺ 362.2. 10 2-chloro-N-(2-fluorobenzyl)thieno[3,2-d]pyrimidin-4-amine

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.73 (d, J = 5.4 Hz, 1H), 7.49 (td,J = 7.6, 1.6 Hz, 1H), 7.35 (d, J = 5.3 Hz, 1H), 7.34 - 7.27 (m, 1H), 7.14 (td, J = 7.5, 1.1 Hz, 1H), 7.12 - 7.05 (m, 1H), 5.47 (br. s, 1H), 4.91 (d, J = 5.6 Hz, 2H). HRMS (ES) C₁₃H₁₀N₃FCIS [M+H]⁺ 294.0260. 11 N⁴-(2-fluorobenzyl)-N²-isopropylthieno[3,2-d]pyrimidine-2,4-diamine

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.54 (d,J = 5.3 Hz, 1H), 7.42 (td, J = 7.5, 1.5 Hz, 1H), 7.33 - 7.21 (m, 1H), 7.17 - 7.01 (m, 3H), 5.12 (br. s, 1H), 5.08 (br. s, 1H), 4.85 (d, J = 5.8 Hz, 2H), 4.28 - 4.04 (m, 1H), 1.23 (d, J = 6.5 Hz, 6H). HRMS (ES) C₁₆H₁₈N₄FS [M+H]⁺ 317.1225.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.54 (d, J = 5.3 Hz, 1H), 7.42 - 7.27 (m, 5H), 7.12 (d, J = 5.3 Hz, 1H), 5.26 (br. s, 1H), 5.16 (br. s, 1H), 4.80 (d, J = 5.6 Hz, 2H), 4.26 - 4.12 (m, 1H), 1.23 (d, J = 6.5 Hz, 6H). HRMS (ES) C₁₆H₁₉N₄S [M+H]⁺ 299.1329.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.52 (d, J = 5.3 Hz, 1H), 7.34 - 7.28 (m, 2H), 7.11 (d, J = 5.3 Hz, 1H), 6.91 - 6.86 (m, 2H), 4.98 (br. s, 1H), 4.92 (br. s, 1H), 4.72 (d, J = 5.5 Hz, 2H), 4.27 -4.14 (m, 1H), 3.81 (s, 3H), 1.24 (d, J = 6.5 Hz, 6H). HRMS (ES) C₁₇H₂₁N₄OS [M+H]⁺ 329.1431.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.55 (d,J = 5.3 Hz, 1H), 7.31 (td, J = 7.9, 5.9 Hz, 1H), 7.18 - 7.06 (m, 3H), 6.98 (td, J = 8.4, 2.6 Hz, 1H), 5.07 (br. s, 1H), 4.84 (br. s, 1H), 4.79 (d, J = 5.7 Hz, 2H), 4.20 - 4.09 (m, 1H), 1.21 (d, J = 6.5 Hz, 6H). HRMS (ES) C₁₆H₁₈N₄FS [M+H]⁺ 317.1226.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.55 (d, J = 5.3 Hz, 1H), 7.38 - 7.32 (m, 2H), 7.12 (d, J = 5.3 Hz, 1H), 7.07 - 6.99 (m, 2H), 5.00 (br. s, 1H), 4.89 (br. s, 1H), 4.76 (d, J = 5.5 Hz, 2H), 4.23 -4.10 (m, 1H), 1.23 (d, J = 6.5 Hz, 6H). HRMS (ES) C₁₆H₁₈N₄FS [M+H]⁺ 317.1230.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.53 (d,J = 5.3 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 7.11 (d, J = 5.3 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.94 - 6.91 (m, 1H), 6.84 (dd, J = 8.2, 2.1 Hz, 1H), 5.02 (br. s, 1H), 4.85 (br. s, 1H), 4.77 (d, J = 5.6 Hz, 2H), 4.24 - 4.13 (m, 1H), 3.80 (s, 3H), 1.23 (d, J = 6.5 Hz, 6H). HRMS (ES) C₁₇H₂₁N₄OS [M+H]⁺ 329.1427.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.55 (d, J = 5.3 Hz, 1H), 7.45 (dd, J = 5.6, 3.8 Hz, 1H), 7.39 (dd, J = 5.5, 3.8 Hz, 1H), 7.25 -7.20 (m, 2H), 7.11 (d, J = 5.3 Hz, 1H), 5.16 (br. s, 1H), 4.89 (d, J = 5.9 Hz, 2H), 4.84 (br. s, 1H), 4.22 - 4.09 (m, 1H), 1.22 (d, J = 6.5 Hz, 6H). HRMS (ES) C₁₆H₁₈N₄S³⁵CI [M+H]⁺ 333.0934.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.56 (d,J= 5.3 Hz, 1H), 7.37 (s, 1H), 7.29 - 7.23 (m, 3H), 7.12 (d, J = 5.3 Hz, 1H), 5.09 (br. s, 1H), 4.91 (br. s, 1H), 4.77 (d, J = 5.6 Hz, 2H), 4.21 - 4.09 (m, 1H), 1.21 (d, J = 6.5 Hz, 6H). HRMS (ES) C₁₆H₁₈N₄S³⁵CI [M+H]⁺ 333.0930.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.55 (d,J = 5.3 Hz, 1H), 7.31 (s, 4H), 7.12 (d, J = 5.3 Hz, 1H), 5.05 (br. s, 1H), 4.92 (br. s, 1H), 4.76 (d, J = 5.8 Hz, 2H), 4.22 - 4.08 (m, 1H), 1.22 (d, J = 6.5 Hz, 6H). HRMS (ES) C₁₆H₁₈N₄S³⁵CI [M+H]⁺ 333.0930.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.53 (d,J= 5.3 Hz, 1H), 7.35 (dd, J = 7.3, 1.5 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.10 (d, J = 5.3 Hz, 1H), 6.96 - 6.89 (m, 2H), 4.79 (d, J = 5.7 Hz, 2H), 4.29 -4.17 (m, 1H), 3.90 (s, 3H), 1.26 (d, J = 6.5 Hz, 6H). HRMS (ES) C₁₇H₂₁N₄OS [M+H]⁺ 329.1440.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.74 (d,J = 5.4 Hz, 1H), 7.57 - 7.51 (m, 1H), 7.45 - 7.38 (m, 1H), 7.36 (d, J = 5.4 Hz, 1H), 7.30 - 7.24 (m, 2H), 5.52 (br. s, 1H), 4.95 (d, J = 5.9 Hz, 2H). HRMS (CI) C₁₃H₉N₃Cl₂S [M+H]⁺ 309.9959.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.66 (s, 1H), 7.71 (d, J= 5.4 Hz, 1H), 7.49 - 7.40 (m, 2H), 7.33 - 7.24 (m, 1H), 7.15 - 7.04 (m, 2H), 5.40 (br. s, 1H), 4.94 (d, J = 5.7 Hz, 2H). HRMS (CI) C₁₃H₁₀N₃FS [M+H]⁺ 260.0660.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.68 (s, 1H), 7.73 (d,J= 5.4 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H), 7.46 (d, J = 5.4 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 5.29 (br. s, 1H), 5.10 (d, J = 5.6 Hz, 2H). HRMS (CI) C₁₄H₁₀N₃F₃S [M+H]⁺ 310.0618.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.66 (s, 1H), 7.73 (d,J= 5.4 Hz, 1H), 7.53 (dd, J = 7.5, 1.4 Hz, 1H), 7.45 (d, J = 5.4 Hz, 1H), 7.38 - 7.32 (m, 1H), 7.32 - 7.24 (m, 2H), 5.28 (br. s, 1H), 4.98 (d, J = 5.9 Hz, 2H). HRMS (CI) C₁₄H₁₀N₃F₃OS [M+H]⁺ 326.0568.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.58 (d, J= 5.3 Hz, 1H), 7.15 - 7.09 (m, 2H), 7.04 (t, J = 7.9 Hz, 1H), 6.98 (dd, J = 7.9, 1.3 Hz, 1H), 4.85 (d, J = 5.8 Hz, 2H), 4.43 - 4.08 (m, 1H), 1.20 (d, J = 6.5 Hz, 6H). HRMS (CI) C₁₇H₁₆N₄F₂O₂S [M+H]⁺ 379.1038.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.54 (d,J= 5.3 Hz, 1H), 7.11 (d, J = 5.3 Hz, 1H), 7.06 - 7.00 (m, 1H), 7.00 - 6.95 (m, 1H), 6.90 (td, J = 8.0, 1.8 Hz, 1H), 4.85 (d, J = 5.4 Hz, 2H), 4.24 -4.14 (m, 1H), 3.89 (s, 3H), 1.23 (d, J = 6.5 Hz, 6H). HRMS (CI) C₁₇H₁₉N₄FOS [M+H]⁺ 347.1339.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.54 (d,J = 5.3 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.22 (dd,J = 8.6, 7.5 Hz, 1H), 7.12 (d, J = 5.3 Hz, 1H), 5.10 (d, J = 5.2 Hz, 2H), 4.34 - 4.23 (m, 1H), 1.27 (d, J = 6.5 Hz, 6H). HRMS (CI) C₁₆H₁₆N₄Cl₂S [M+H]⁺ 367.0538.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.68 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 5.3 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.11 (d, J = 5.3 Hz, 1H), 5.09 (br. s, 1H), 5.01 (d, J = 5.7 Hz, 2H), 4.79 (br. s, 1H), 4.20 - 4.06 (m, 1H), 1.18 (d, J = 6.5 Hz, 6H). HRMS (CI) C₁₇H₁₇N₄F₃S [M+H]⁺ 367.1196.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.55 (d,J = 5.3 Hz, 1H), 7.48 (dd, J = 7.4, 1.3 Hz, 1H), 7.35 - 7.23 (m, 3H), 7.11 (d, J = 5.3 Hz, 1H), 5.08 (br. s, 1H), 4.88 (d, J = 5.9 Hz, 2H), 4.83 (br. s, 1H), 4.22 - 4.07 (m, 1H), 1.20 (d, J = 6.5 Hz, 6H). HRMS (CI) C₁₇H₁₇N₄F₃OS [M+H]⁺ 383.1149.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.52 (d,J= 5.3 Hz, 1H), 7.25 - 7.19 (m, 2H), 7.08 (d, J = 5.3 Hz, 1H), 7.02 (ddd, J = 9.4, 6.7, 2.8 Hz, 1H), 5.11 (br, s, 1H), 4.97 (d, J = 5.7 Hz, 2H), 4.85 (d, J = 7.0 Hz, 1H), 4.34 - 4.21 (m, 1H), 1.25 (d, J = 6.5 Hz, 6H). HRMS (CI) C₁₆H₁₆N₄FCIS [M+H]⁺ 351.0842.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.61 (s, 1H), 7.64 (d,J= 5.5 Hz, 1H), 7.37 (d, J = 5.5 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.16 (s, 1H), 7.11 (d, J = 7.9 Hz, 1H), 2.42 (s, 3H), 2.26 (s, 3H). HRMS (CI) C₁₄H₁₃N₃S [M+H]⁺ 256.0910.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.46 (d,J = 5.4 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.11 (s, 1H), 7.06 (dd, J = 6.5, 4.8 Hz, 2H), 4.65 (br. s, 1H), 4.23 - 4.11 (m, 1H), 2.38 (s, 3H), 2.25 (s, 3H), 1.21 (d, J = 6.4 Hz, 6H). HRMS (CI) C₁₇H₂₀N₄S [M+H]⁺ 313.1488.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.52 (d,J= 5.3 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.41- 7.35 (m, 1H), 7.24 - 7.18 (m, 3H), 5.17 - 5.06 (m, 2H), 4.89 (d, J = 5.8 Hz, 2H), 2.99 (s, 3H), 1.14 (d, J = 6.8 Hz, 6H). HRMS (CI) C₁₇H₁₉N₄CIS [M+H]⁺ 347.1097.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.58 (s, 1H), 7.70 (d, J= 5.4 Hz, 1H), 7.39 (d, J = 5.4 Hz, 1H), 6.76 (t, J = 5.5 Hz, 1H), 3.64 (dd, J = 12.1, 6.2 Hz, 2H), 3.47 - 3.41 (m, 4H), 2.48 (t, J = 8.1 Hz, 2H), 2.14 - 2.01 (m, 2H), 1.91 - 1.82 (m, 2H). HRMS (CI) C₁₃H₁₆N₄OS [M+H]⁺ 277.1129.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.54 (d,J= 5.3 Hz, 1H), 7.35 (d, J = 7.1 Hz, 1H), 7.22 (td, J = 7.9, 1.7 Hz, 1H), 7.11 (d, J = 5.3 Hz, 1H), 6.91 - 6.84 (m, 2H), 6.51 (br. s, 1H), 5.90 (br. s, 1H), 4.66 (d, J = 6.2 Hz, 2H), 3.87 (s, 3H), 3.57 (dd, J = 12.1, 6.1 Hz, 2H), 3.39 (t, J = 6.9 Hz, 4H), 2.44 (t, J = 8.1 Hz, 2H), 2.10 - 1.99 (m, 2H), 1.84 - 1.72 (m, 2H). HRMS (ES) C₂₁H₂₆N₅O₂S [M+H]⁺ 412.1797.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.54 (d, J = 5.3 Hz, 1H), 7.32 - 7.27 (m, 4H), 7.25 - 7.13 (m, 2H), 6.06 (br. s, 1H), 4.94 (s, 2H), 3.54-3.47 (m, 2H), 3.38-3.30 (m, 4H), 3.18 (s, 3H), 2.41 (t, J = 8.1 Hz, 2H), 2.04 - 1.95 (m, 2H), 1.76 - 1.67 (m, 2H). HRMS (CI) C₂₁H₂₅N₅OS [M+H]⁺ 396.1868.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 9.67 (br. s, 1H), 8.40 (s, 1H), 8.06 (d, J = 5.6 Hz, 1H), 7.81 (dd, J = 5.4, 3.7 Hz, 1H), 7.74 (dd, J = 5.1, 3.7 Hz, 1H), 7.71 - 7.65 (m, 2H), 7.53 (d, J = 5.6 Hz, 1H). HRMS (CI) C₁₄H₈N₃F₃OS [M+H]⁺ 324.0401.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.59 (s, 1H), 7.71 (d,J= 5.4 Hz, 1H), 7.46 - 7.36 (m, 3H), 7.26 - 7.18 (m, 2H), 5.83 (p, J = 6.9 Hz, 1H), 5.40 (d, J = 5.2 Hz, 1H), 1.68 (d, J = 6.9 Hz, 3H). HRMS (CI) C₁₄H₁₂N₃CIS [M+H]⁺ 290.0525.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 9.89 (s, 1H), 8.50 (s, 1H), 8.05 (d, J = 5.6 Hz, 1H), 7.85 - 7.80 (m, 1H), 7.52 (d, J = 5.6 Hz, 1H), 7.50 - 7.46 (m, 2H), 7.42 (ddd, J = 7.6, 5.7, 2.9 Hz, 1H). HRMS (CI) C₁₃H₈N₃OCIS [M+H]⁺ 290.0161.

Synthesised via Route 1 ¹H NMR (250 MHz, CDCl₃) δ (ppm) 7.68 (d, J = 7.7 Hz, 1H), 7.61 - 7.43 (m, 3H), 7.37 (t, J = 7.0 Hz, 1H), 7.09 (d, J = 5.3 Hz, 1H), 5.44 (br. s, 1H), 5.30 (br. s, 1H), 5.04 (d, J = 5.5 Hz, 2H), 1.34 (s, 9H). HRMS (CI) C₁₈H₁₉N₄F₃S [M+H]⁺ 381.1339.

Synthesised via Route 1 ¹H NMR (250 MHz, CDCl₃) δ (ppm) 7.69 (d, J = 7.7 Hz, 1H), 7.63 - 7.55 (m, 2H), 7.50 (t, J = 7.2 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.14 (d, J = 5.3 Hz, 1H), 5.32 - 5.10 (m, 2H), 5.00 (d, J = 5.7 Hz, 2H), 4.12 (qd, J = 9.2, 6.9 Hz, 2H). HRMS (CI) C₁₆H₁₂N₄F₆S [M+H]⁺ 407.0744.

Synthesised via Route 1 ¹H NMR (500 MHz, CDCl₃) δ (ppm) 7.70 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 5.3 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 5.3 Hz, 1H), 5.42 (br. s, 1H), 5.20 (br. s, 1H), 5.05 (d, J = 5.9 Hz, 2H), 2.84 - 2.77 (m, 1H), 0.80 - 0.74 (m, 2H), 0.57 - 0.51 (m, 2H). HRMS (CI) C₁₇H₁₅N₄F₃S [M+H]⁺ 365.1029.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.58 (s, 1H), 7.76 - 7.70 (m, 2H), 7.48 (t, J = 7.6 Hz, 1H), 7.44 (d, J = 5.6 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 5.30 (s, 2H), 3.47 (s, 3H). HRMS (ES) C₁₅H₁₃N₃F₃S [M+H]⁺ 324.0792.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.67 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 5.3 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.39 - 7.30 (m, 2H), 7.10 (d, J = 5.3 Hz, 1H), 4.98 - 4.71 (m, 2H), 4.30 - 4.17 (m, 1H), 3.84 (dd,J= 13.8, 6.6 Hz, 2H), 3.18 (t, J= 7.2 Hz, 2H), 1.27 (d, J = 6.5 Hz, 6H). HRMS (CI) C₁₈H₁₉N₄F₃S [M+H]⁺ 381.1353.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.74 (d, J= 5.3 Hz, 1H), 7.70 (d, J = 7.8 Hz, 2H), 7.55 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 5.3 Hz, 1H), 5.46 (br. s, 1H), 5.06 (d, J = 5.7 Hz, 2H). HRMS (CI) C₁₄H₁₀N₃F₃Cl₂S [M+H]⁺ 378.9921.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.93 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 5.3 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.27 - 7.23 (m, 1H), 7.19 (td, J = 7.6, 1.7 Hz, 1H), 6.16 (br. s, 1H), 1.41 (d, J = 7.3 Hz, 4H). HRMS (CI) C₁₅H₁₁N₃Cl₂S [M+H]⁺ 336.0118.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.78 (dd, J = 7.1, 2.2 Hz, 1H), 7.49 (d, J = 5.3 Hz, 1H), 7.32 (dd, J = 7.2, 1.9 Hz, 1H), 7.22 - 7.13 (m, 2H), 7.01 (d, J = 5.3 Hz, 1H), 5.81 (s, 1H), 4.77 (d, J = 6.5 Hz, 1H), 4.36 - 4.21 (m, 1H), 1.42 - 1.30 (m, 4H), 1.29 (d, J = 6.5 Hz, 6H). HRMS (CI) C₁₈H₁₉N₄CIS [M+H]⁺ 359.1099.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.78 - 7.70 (m, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 5.5 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 5.28 (s, 2H), 3.44 (s, 3H). HRMS (CI) C₁₅H₁₁N₃F₃ClS [M+H]⁺ 358.0397.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.70 (d, J= 7.7 Hz, 1H), 7.57 (d, J = 5.5 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 5.5 Hz, 1H), 5.20 (s, 2H), 4.67 (d, J = 7.0 Hz, 1H), 4.04 (dq, J = 13.4, 6.5 Hz, 1H), 3.43 (s, 3H), 1.13 (d, J = 6.4 Hz, 6H). HRMS (ES) C₁₈H₂₀N₄F₃S [M+H]⁺ 381.1351.

Synthesised via Route 2 ¹H NMR (400 MHz, DMSO) δ (ppm) 8.44 - 8.37 (m, 2H), 8.15 (d, J = 5.4 Hz, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.41 (d, J = 5.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 7.9 Hz, 1H), 4.87 (d, J = 2.7 Hz, 2H), 3.87 (s, 3H). HRMS (ES) C₁₅H₁₃N₃F₃OS [M+H]⁺ 340.0728.

Synthesised via Route 1 ¹H NMR (400 MHz, DMSO) δ (ppm) 8.93 (d, J = 7.0 Hz, 1H), 8.21 (d, J = 5.4 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.65 (t, J = 7.7 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 5.4 Hz, 1H), 5.75 - 5.62 (m, 1H), 1.54 (d, J = 6.9 Hz, 3H). HRMS (ES) C_(ls)H₁₂N₃F₃ClS [M+H]⁺ 358.0391.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.66 (d,J = 7.8 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 5.3 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 5.3 Hz, 1H), 5.71 (p, J = 6.5 Hz, 1H), 4.98 (br. s, 1H), 4.65 (br. s, 1H), 4.06 - 3.90 (m, 1H), 1.61 (d, J = 6.8 Hz, 3H), 1.15 (d, J = 6.5 Hz, 3H), 0.90 (d, J = 6.1 Hz, 3H). HRMS (ES) C₁₈H₂₀N₄F₃S [M+H]⁺ 381.1356.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.58 (s, 1H), 7.71 (dd, J = 6.8, 4.0 Hz, 2H), 7.49 - 7.41 (m, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.29 (s, 2H), 3.85 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H). HRMS (ES) C₁₆H₁₅N₃F₃S [M+H]⁺ 338.0930.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.75 - 7.63 (m, 3H), 7.52 (t,J= 7.5 Hz, 1H), 7.44 - 7.33 (m, 2H), 5.22 (br. s, 1H), 5.09 (d, J = 5.3 Hz, 2H), 2.66 (s, 3H). HRMS (ES) C₁₅H₁₃N₃F₃S [M+H]⁺ 324.0780.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.82 (d,J = 5.4 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.54 (dd, J = 9.3, 3.9 Hz, 2H), 7.42 (t, J = 7.7 Hz, 1H), 5.49 (br. s, 1H), 5.10 (d,J= 5.9 Hz, 2H). HRMS (ES) C₁₅H₁₀N₃F₆S [M+H]⁺ 378.0493.

Synthesised via Route 4 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.80 - 7.62 (m, 5H), 7.55 (t, J = 7.5 Hz, 1H), 7.44 (dd, J = 16.4, 8.2 Hz, 2H), 6.28 (br. s, 1H), 5.07 (d, J = 5.1 Hz, 2H). HRMS (ES) C₁₆H₁₂N₃F₃Cl [M+H]⁺ 338.0670.

Synthesised via Route 4 ¹H NMR (400 MHz, CDCl3) δ (ppm) 13.42 (s, 1H), 8.30 - 8.11 (m, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.79 - 7.61 (m, 2H), 7.52 (dd, J = 14.7, 7.8 Hz, 2H), 7.43 (t, J = 7.5 Hz, 1H), 7.32 (m, 1H), 5.10 (d, J = 5.4 Hz, 2H), 4.20 - 4.05 (m, 1H), 1.57 (d, J = 6.6 Hz, 2H), 1.20 (d, J = 6.6 Hz, 4H). HRMS (ES) C₁₉H₂₀N₄F₃ [M+H]⁺ 361.1648.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.21 (d,J = 8.2 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.61 (dd, J = 16.5, 6.7 Hz, 2H), 7.30 (dd, J = 9.8, 4.0 Hz, 1H), 7.17 (d, J = 5.3 Hz, 1H), 6.82 (br. s, 1H), 4.92 (br. s, 1H), 4.27 - 4.07 (m, 1H), 1.27 (d, J = 6.6 Hz, 6H). HRMS (ES) C₁₆H₁₆N₄F₃S [M+H]⁺ 353.1039.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.69 (s, 1H), 7.76 (d,J = 5.4 Hz, 1H), 7.71 (dd, J = 8.6, 5.5 Hz, 1H), 7.49 (d, J = 5.4 Hz, 1H), 7.42 (dd, J = 8.9, 2.7 Hz, 1H), 7.23 (td, J = 8.2, 2.7 Hz, 1H), 5.34 (br. s, 1H), 5.08 (d, J = 5.7 Hz, 2H). HRMS (ES) C₁₄H₁₀N₃F₄S [M+H]⁺ 328.0527.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.81 (d,J = 4.4 Hz, 1H), 8.70 (s, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 5.4 Hz, 1H), 7.47 (d, J = 5.4 Hz, 1H), 7.43 (dd, J = 7.5, 5.2 Hz, 1H), 7.02 (br. s, 1H), 5.14 (d, J = 3.8 Hz, 2H). HRMS (ES) C₁₃H₁₀N₄F₃S [M+H]⁺ 311.0572.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.83 (d,J = 5.6 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.55 (d, J = 5.6 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 5.32 (s, 2H), 3.51 (s, 3H). HRMS (ES) C₁₆H₁₂N₃F₆S [M+H]⁺ 392.0651.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.72 (d,J = 7.7 Hz, 1H), 7.68 (d, J = 5.2 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 6.7 Hz, 2H), 7.29 (d, J = 7.7 Hz, 1H), 5.29 (s, 2H), 3.45 (s, 3H), 2.59 (s, 3H). HRMS (ES) C₁₆H₁₅N₃F₃S [M+H]⁺ 338.0935.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.73 (d,J = 7.7 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.4 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.20 (s, 1H), 5.27 (s, 2H), 3.44 (s, 3H), 2.59 (s, 3H). HRMS (ES) C₁₇H₁₄N₃F₆S [M+H]⁺ 406.0808.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.72 - 7.63 (m, 2H), 7.60 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 5.4 Hz, 1H), 5.83 (p, J = 6.6 Hz, 1H), 5.19 (d, J = 5.7 Hz, 1H), 2.50 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H). HRMS (ES) C₁₆H₁₅N₃F₃S [M+H]⁺ 338.0933.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.70 (d,J = 7.8 Hz, 1H), 7.66 (d, J = 5.5 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 5.5 Hz, 1H), 6.62 (q, J = 6.8 Hz, 1H), 3.20 (s, 3H), 2.57 (s, 3H), 1.67 (d, J = 6.9 Hz, 3H). HRMS (ES) C₁₇H₁₇N₃F₃S [M+H]⁺ 352.1091.

Synthesised via Route 1 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.74 (d,J = 5.6 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.69 - 7.58 (m, 2H), 7.46 (t, J = 7.5 Hz, 1H), 7.35 (d, J = 5.5 Hz, 1H), 6.54 (q, J = 6.8 Hz, 1H), 3.11 (s, 3H), 1.70 (d, J = 6.8 Hz, 3H). HRMS (ES) C₁₆H₁₄N₃F₃CIS [M+H]⁺ 372.0541.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.72 (d,J = 7.8 Hz, 1H), 7.67 (dd, J = 6.6, 4.4 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.28 (s, 1H), 6.66 (q, J = 6.8 Hz, 1H), 4.00 (s, 3H), 3.08 (s, 3H), 1.69 (d, J = 6.8 Hz, 3H). HRMS (ES) C₁₇H₁₇N₃F₃OS [M+H]⁺ 368.1037.

Synthesised via Route 2 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.70 (d,J = 7.8 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.01 (s, 1H), 6.56 (q, J = 6.8 Hz, 1H), 3.14 (s, 3H), 2.56 (d, J = 0.7 Hz, 3H), 2.54 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H). HRMS (ES) C₁₈H₁₉N₃F₃S [M+H]⁺ 366.1247.

Synthesised via Route 3 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.70 (d,J = 7.8 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.14 (s, 1H), 6.60 (q, J = 6.8 Hz, 1H), 3.19 (s, 3H), 2.55 (s, 3H), 1.69 (s, 6H), 1.66 (d, J = 6.9 Hz, 3H). HRMS (ES) C₂₀H₂₃N₃F₃OS [M+H]⁺ 410.1505.

Synthesised via Route 5 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.70 (s, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.80 - 7.73 (m, 1H), 7.73 - 7.66 (m, 2H), 7.52 - 7.46 (m, 1H), 7.40 (dd, J = 8.9, 2.6 Hz, 1H), 7.20 (td, J = 8.3, 2.6 Hz, 1H), 6.14 (br. s, 1H), 5.07 (d, J = 5.7 Hz, 2H). HRMS (ES) C₁₆H₁₂N₃F₄ [M+H]⁺ 322.0869.

Synthesised via Route 5 ¹H NMR (400 MHz, DMSO) δ (ppm) 8.75 (t, J = 5.7 Hz, 1H), 8.28 (d, J = 7.8 Hz, 1H), 7.75 (t, J = 8.2 Hz, 1H), 7.68 - 7.61 (m, 2H), 7.58 (dd, J = 8.6, 5.7 Hz, 1H), 7.52 - 7.44 (m, 2H), 4.93 (d, J = 5.4 Hz, 2H), 2.39 (s, 3H). HRMS (ES) C₁₇H₁₄N₃F₄ [M+H]⁺ 336.1127.

Synthesised via Route 2 ¹H NMR (400 MHz, DMSO) δ (ppm) 8.41 (d, J = 5.6 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.82 - 7.72 (m, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 5.6 Hz, 1H), 6.37 (q, J = 6.8 Hz, 1H), 3.24 (s, 3H), 1.68 (d, J = 6.9 Hz, 3H). HRMS (ES) C₁₇H₁₄N₄F₃S [M+H]⁺ 363.0888.

Synthesised via Route 5 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.70 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.78 - 7.69 (m, 1H), 7.59 (dd, J = 8.4, 5.5 Hz, 1H), 7.48 (dd, J = 8.8, 2.5 Hz, 1H), 7.41 - 7.33 (m, 1H), 7.31 - 7.22 (m, 1H), 5.13 (s, 2H), 3.33 (s, 4H). HRMS (ES) C₁₇H₁₄N₃F₄ [M+H]⁺ 336.1126.

Synthesised via Route 1 1H NMR (400 MHz, Chloroform-d) δ (ppm) 7.68 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.55 (dd, J = 5.3, 1.0 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.12 (dd, J = 5.3, 1.0 Hz, 1H), 5.22 (m, 1H), 5.11 (br.s, 1H), 5.00 (d, J = 6.0 Hz, 2H), 3.41 (q, J = 6.5 Hz, 2H), 3.35 (td, J = 7.0, 3.2 Hz, 4H), 2.38 (t, J = 8.1 Hz, 2H), 2.07 - 1.93 (m, 2H), 1.76 (p, J = 6.8 Hz, 2H). HRMS (Cl+) C21H22F₃N5OS [M+H]⁺ 450.1582.

Synthesised via Route 1 1H NMR (400 MHz, CDCl3) δ (ppm) 7.68 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.54 (d, J = 5.3 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 5.3 Hz, 1H), 5.30 (t, J = 4.7 Hz, 1H), 5.05 (d, J = 5.0 Hz, 1H), 5.01 (d, J = 5.5 Hz, 2H), 3.49 (dd, J = 11.6, 5.9 Hz, 2H), 2.49 (t, J = 6.1 Hz, 2H), 2.24 (s, 7H). HRMS (ES+) C18H20F3N5S [M+H]⁺ 396.1460

Synthesised via Route 1 1H NMR (400 MHz, CDCl3) δ (ppm) 7.68 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 5.3 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.37 (dd, J = 17.4, 9.9 Hz, 1H), 7.13 (d, J = 5.3 Hz, 1H), 5.38 (s, 1H), 5.16 (s, 1H), 5.02 (d, J = 5.9 Hz, 2H), 3.84 -3.61 (m, 5H), 3.50 (dd, J = 10.1, 4.3 Hz, 2H), 2.54 (dd, J = 11.2, 5.1 Hz, 2H), 2.45 (s, 4H). HRMS (Cl+) C20H22F3N5OS [M+H]⁺ 438.1583

Synthesised via Route 1 1H NMR (400 MHz, CDCl3) δ (ppm) 7.68 (d, J = 7.8 Hz, 1H), 7.62 (s, 1H), 7.55 (d, J = 5.3 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 5.3 Hz, 1H), 5.40 (t, J = 4.9 Hz, 1H), 5.06 (d, J = 4.9 Hz, 1H), 5.01 (d, J = 5.6 Hz, 2H), 3.57 (dd, J = 11.8, 6.0 Hz, 2H), 2.74 (t, J = 6.0 Hz, 2H), 2.62 (s, 4H). HRMS (ES+) C20H22F3N5S [M+H]⁺ 422.1612

Synthesised via Route 1 1H NMR (400 MHz, CDCl3) δ (ppm) 7.60 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.47 (t, J = 4.9 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 5.3 Hz, 1H), 5.37 (s, 1H), 5.16 (s, 1H), 4.94 (d, J = 5.9 Hz, 2H), 3.41 (dd, J = 11.5, 5.9 Hz, 2H), 2.47 (dd, J = 12.0, 5.9 Hz, 3H), 2.41 (dd, J = 13.8, 7.7 Hz, 5H), 1.18 (t, J = 7.1 Hz, 1H). HRMS (Cl+) C21H25F3N6S [M+H]⁺ 451.1892

Synthesised via Route 1 1H NMR (400 MHz, CDCl3) δ (ppm) 8.58 (s, 1H), 7.73 (d, J = 5.6 Hz, 2H), 7.48 (t, J = 7.5 Hz, 1H), 7.43 (d, J = 5.6 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 3.47 (s, 3H), 1.64 (s, 2H). HRMS (ES+) C18H17F3N4S [M+H]⁺ 379.1196

Synthesised via Route 1 1H NMR (400 MHz, CDCl3) δ (ppm) 7.67 (t, J = 8.4 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.57 (d, J = 5.5 Hz, 1H), 7.49 (q, J = 7.5 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 5.3 Hz, 1H), 5.10 (t, J = 5.6 Hz, 1H), 5.00 (d, J = 5.9 Hz, 2H), 3.83 - 3.67 (m, 8H). HRMS (ES+) C18H17F3N4OS [M+H]⁺ 395.1161

Synthesised via Route 1 1H NMR (400 MHz, CDCl3) δ (ppm) 7.68 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 5.3 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 5.3 Hz, 1H), 5.09 - 5.03 (m, 1H), 5.00 (d, J = 5.8 Hz, 2H), 3.90 - 3.77 (m, 4H), 2.52 - 2.41 (m, 4H), 2.33 (s, 3H). HRMS (Cl+) C19H20F3N5S [M+H]⁺ 408.1475

Synthesised via Route 3 1H NMR (400 MHz, CDCl3) δ (ppm) 8.46 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.4 Hz, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 5.81 (p, J = 6.7 Hz, 1H), 4.95 (d, J = 5.9 Hz, 1H), 1.65 (d, J = 6.7 Hz, 3H). HRMS (Cl+) C15H11F3IN3S [M+H]⁺ 449.9759

Synthesised via Route 2 1H NMR (400 MHz, CDCl3) δ (ppm) 8.62 (s, 1H), 8.05 (dd, J = 7.9, 1.2 Hz, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 5.4 Hz, 1H), 7.61 (td, J= 7.6, 1.3 Hz, 1H), 7.50 (td, J = 7.8, 1.2 Hz, 1H), 7.40 (d, J = 5.4 Hz, 1H), 6.05 (t, J = 5.9 Hz, 1H), 5.19 (d, J = 6.4 Hz, 2H), 3.24 (s, 3H). HRMS (Cl+) C14H13N3O2S2 [M+H]⁺ 320.0533

Synthesised via Route 3 1H NMR (400 MHz, CDCl3) δ (ppm) 8.55 (s, 1H), 7.76 - 7.68 (m, 3H), 7.66 (d, J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.50 - 7.42 (m, 3H), 7.39 (t, J = 7.5 Hz, 1H), 5.86 (p, J = 6.7 Hz, 1H), 5.08 (d, J = 6.0 Hz, 1H), 1.68 (d, J = 6.7 Hz, 3H). HRMS (Cl+) C21H16F3N3S [M+H]⁺ 400.1104

Synthesised via Route 3 1H NMR (400 MHz, CDCl3) δ (ppm) 8.49 (s, 1H), 7.73 - 7.63 (m, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.51 (dd, J = 18.3, 10.5 Hz, 1H), 7.41 - 7.32 (m, 1H), 7.03 (s, 1H), 5.89 - 5.75 (m, 1H), 5.00 (d, J = 5.7 Hz, 1H), 2.26 - 2.16 (m, 1H), 1.31 - 1.19 (m, 1H), 1.20 - 1.11 (m, 2H), 0.87 (tt, J = 14.7, 7.2 Hz, 2H). HRMS (Cl+) C18H16F3N3S [M+H]⁺ 364.1094

Synthesised via Route 3 1H NMR (400 MHz, CDCl3) δ (ppm) 8.63 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.69 (t, J = 10.1 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 5.96 - 5.80 (m, 1H), 5.46 (s, 1H), 1.70 (d, J = 6.7 Hz, 3H), 1.26 (d, J = 7.6 Hz, 1H). HRMS (Cl+) C16H11F3N4S [M+H]⁺ 349.074

Synthesised via Route 2 1H NMR (400 MHz, CDCl3) δ (ppm) 8.58 (s, 1H), 8.54 (d, J = 4.3 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 5.4 Hz, 1H), 7.39 (dd, J = 10.1, 5.0 Hz, 2H), 5.41 (d, J = 5.2 Hz, 1H), 5.05 (d, J = 6.1 Hz, 2H). HRMS (ES+) C13H9F3N4S [M+H]⁺ 311.0575

Synthesised via Route 1 1H NMR (400 MHz, CDCl3) δ (ppm) 7.77 (d, J = 5.4 Hz, 1H), 7.73 - 7.66 (m, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.37 (d, J = 5.4 Hz, 1H), 5.88 (b, 1H), 5.04 (d, J = 6.2 Hz, 2H). HRMS (Cl+) C14H9CIN4S [M+H]⁺ 301.0322

Synthesised via Route 2 1H NMR (400 MHz, CDCl3) δ (ppm) 8.61 (s, 1H), 7.64 (d, 1H, J = 7.9 Hz), 7.65 (d, 1H, J = 7.8 Hz), 7.52 (t, 1H, J = 7.9 Hz), 7.38 (t, 1H, J = 7.8 Hz), 7.32 (s, 1H), 5.86 (m, 1H, J = 6.6 Hz)), 5.07 (s, 1H), 2.44 (s, 3H), 1.67 (d, 3H, J = 6.6 Hz). HRMS: (Cl+, NH3) C16H15F3N3S [M+H]⁺ 338.0945

Synthesised via Route 2 1H NMR (400 MHz, CDCl3) δ (ppm) 8.68 (s, 1H), 7.72 (s, 1H), 7.71 (d, 1H, J = 8.8 Hz), 7.64 (d, 1H, J = 7.8 Hz), 7.59 (t, 1H, J = 8.8 Hz), 7.54 (t, 1H, J = 7.8 Hz), 5.86 (m, 1H), 5.14 (s, 1H), 1.68 (s, 3H). HRMS: (Cl+, NH3) C15H11BrF3N3S [M+H]⁺ 401.9896.

Synthesised via Route 2 1H NMR (400 MHz, CDCl3) δ (ppm) 8.68 (s, 1H), 8.31 (s, 1H), 7.70 (d, 1H, J = 7.8 Hz), 7.60 (d, 1H, J = 7.7 Hz), 7.55 (t, 1H, J = 7.7 Hz), 7.41 (t, 1H, J = 7.8 Hz), 5.85 (m, 1H), 5.24 (s, 1H), 1.68 (d, 3H). HRMS: (Cl+, CH4) C16H11F3N4S [M+H]⁺ 349.0739.

Synthesised via Route 1 1H NMR (400 MHz, MeOD) δ (ppm) 7.53 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 5.3 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 5.3 Hz, 1H), 5.97 (s, 1H), 5.14 (s, 1H), 4.81 (d, J = 5.6 Hz, 2H), 4.09 (dq, J = 13.2, 6.5 Hz, 1H), 1.15 (d, J = 6.5 Hz, 6H). HRMS: (ES) C17H18F3N4S [M + H]⁺ 367.1203.

Synthesised via Route 4 1H NMR (400 MHz, CDCl3) δ (ppm) 8.01 (d, J = 6.9 Hz, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.50 - 7.47 (m, 2H), 7.47 - 7.44 (m, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 4.85 (s, 2H), 4.13 - 4.01 (m, 1H), 2.97 (s, 3H), 1.109 (d, J = 6.4 Hz 6H). HRMS: (ES) C19H23N4O2S [M + H]⁺ 371.1539.

Synthesised via Route 4 1H NMR (400 MHz, CDCl3) δ (ppm) 7.65 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 5.6 Hz, 2H), 7.48 (dd, J = 6.9, 1.2 Hz, 1H), 7.42 (d, J = 4.5 Hz, 2H), 7.41 (s, 1H), 7.07 - 7.00 (m, 1H), 6.62 (s, 1H), 4.82 (d, J = 5.0 Hz, 3H), 4.17 (dd, J = 12.4, 6.1 Hz, 1H), 1.14 (d, J = 6.5 Hz, 6H). HRMS: (ES) C19H20F3N4 [M + H]⁺ 361.1639.

Synthesised via Route 4 1H NMR (400 MHz, CDCl3) δ (ppm) 8.04 (dd, J = 7.9, 1.3 Hz, 1H), 7.71 (dd, J = 7.6, 0.8 Hz, 1H), 7.64 - 7.56 (m, 2H), 7.55 -7.47 (m, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.14 - 7.08 (m, 1H), 5.15 (d, J = 5.6 Hz, 2H), 4.29 (dq, J = 13.3, 6.5 Hz, 1H), 3.18 (s, 3H), 1.27 (d, J = 6.5 Hz, 6H). HRMS: (ES) C19H23N4O2S [M + H]⁺ 371.1540.

Synthesised via Route 4 1H NMR (400 MHz, MeOD) δ (ppm) 8.78 (s, 1H), 8.08 (d, J = 6.3 Hz, 1H), 8.07 (s, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 4.95 (s, 2H), 4.12 (dq, J = 12.5, 6.3 Hz, 1H), 1.17 (d, J = 6.4 Hz, 6H). HRMS: (ES) C19H20F3N4 [M + H]⁺ 362.1590.

Synthesised via Route 1 1H NMR (400 MHz, CDCl3) δ (ppm) 7.63 - 7.58 (m, 2H), 7.56 (d, J = 5.3 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 5.3 Hz, 1H), 5.43 (s, 1H), 4.96 (s, 1H), 4.84 (d, J = 5.8 Hz, 2H), 4.07 (tt, J = 13.1, 6.7 Hz, 1H), 1.16 (d, J = 6.5 Hz, 6H). HRMS: (ES) C17H17N5S [M + H]⁺ 324.1281.

Synthesised via Route 1 1H NMR (400 MHz, CDCl3) δ (ppm) 8.03 - 7.99 (m, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.50 (d, J = 5.3 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 5.3 Hz, 1H), 5.88 (s, 1H), 5.10 (d, J = 6.3 Hz, 2H), 4.70 (d, J = 8.0 Hz, 1H), 4.17 (dq, J = 13.0, 6.5 Hz, 1H), 3.14 (s, 3H), 1.20 (d, J = 6.5 Hz, 6H). HRMS: (ES) C17H20N2NaO2S2 [M + Na]⁺ 399.0925.

Synthesised via Route 1 1H NMR (400 MHz, CDCl3) δ (ppm) 7.80 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 5.3 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 5.3 Hz, 1H), 5.82 (s, 1H), 4.82 (d, J = 5.9 Hz, 2H), 4.75 (d, J = 7.9 Hz, 1H), 4.05 (dq, J = 13.1, 6.5 Hz, 1H), 3.00 (s, 3H), 1.12 (d, J = 6.5 Hz, 6H). HRMS: (ES) C17H20N2NaO2S2 [M + Na]⁺ 399.0924.

Synthesised via Route 1 1H NMR (400 MHz, CDCl3) δ (ppm) 8.71 (s, 1H), 7.85 (d, J = 7.1 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 5.3 Hz, 1H), 7.08 (d, J = 5.3 Hz, 1H), 5.69 (s, 1H), 4.84 (d, J = 5.7 Hz, 2H), 4.77 (d, J = 7.6 Hz, 1H), 4.05 (m, 1H), 1.14 (d, J = 6.5 Hz, 6H). HRMS: (ES) C16H16F3N5NaS [M + Na]⁺ 390.0973.

Synthesised via Route 4 1H NMR (400 MHz, DMSO) δ (ppm) 10.35 (s, 1H), 8.38 (s, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.78 - 7.72 (m, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7.37 (s, 1H), 4.84 (d, J = 5.5 Hz, 2H), 4.06 (s, 1H), 1.08 (s, 6H). HRMS: (ES) C19H20N5 [M + H]⁺ 318.1719.

Synthesised via Route 7 1H NMR (400 MHz, CDCl3) δ (ppm) 8.28 (d, J = 3.4 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.57 (d, J = 7.9 Hz, 2H), 7.43 (d, J = 7.0 Hz, 2H), 7.40 (s, 1H), 5.19 (s, 1H), 4.80 (d, J = 5.9 Hz, 2H), 4.17 (m, 1H), 1.18 (d, J = 5.8 Hz, 6H). HRMS: (ES) C18H19N6 [M + H]⁺ 319.1669.

Synthesised via Route 7 1H NMR (400 MHz, CDCl3) δ (ppm) 8.30 (d, J = 4.2 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.41 (dd, J = 8.5, 4.2 Hz, 1H), 5.17 (d, J = 6.5 Hz, 2H), 4.91 (s, 1H), 4.28 - 4.18 (m, 1H), 3.17 (s, 3H), 1.24 (d, J = 6.5 Hz, 6H). HRMS: (ES) C18H22N5O2S [M + H]⁺ 372.1495.

Synthesised via Route 7 1H NMR (400 MHz, CDCl3) δ (ppm) 8.32 - 8.28 (m, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.44 (dd, J = 8.5, 4.2 Hz, 2H), 4.87 (d, J = 6.2 Hz, 2H), 4.18 (dt, J = 13.4, 6.7 Hz, 1H), 3.03 (s, 3H), 1.21 (d, J = 6.5 Hz, 6H). HRMS: (ES) C18H22N5O2S [M + H]⁺ 372.1491.

Synthesised via Route 7 1H NMR (400 MHz, CDCl3) δ (ppm) 8.31 (d, J = 4.2 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.45 (dd, J = 8.5, 4.2 Hz, 1H), 4.85 (d, J = 6.1 Hz, 2H), 4.21 (dq, J = 13.4, 6.7 Hz, 1H), 1.23 (d, J = 6.5 Hz, 6H). HRMS: (ES) C18H19F3N5 [M + H]⁺ 362.1595.

Synthesised via Route 7 1H NMR (400 MHz, CDCl3) δ (ppm) 8.77 (s, 1H), 8.28 (dd, J = 4.2, 1.1 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.43 (dd, J = 8.5, 4.2 Hz, 1H), 4.94 (s, 1H), 4.85 (d, J = 6.2 Hz, 2H), 4.17 (d, J = 6.3 Hz, 1H), 1.20 (d, J = 6.4 Hz, 6H). HRMS: (ES) C17H18F3N6 [M + H]⁺ 363.1546.

Synthesised via Route 6 1H NMR (400 MHz, MeOD) δ (ppm) 8.53 (dd, J = 4.5, 1.6 Hz, 1H), 8.27 (d, J = 7.7 Hz, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.00 (dd, J = 8.0, 4.6 Hz, 1H), 4.77 (s, 2H), 4.11 (s, 1H), 3.28 - 3.26 (m, 1H), 1.12 (d, J = 23.6 Hz, 6H). HRMS: (ES) C18H18N6Na [M + Na]⁺ 341.1489.

Synthesised via Route 6 1H NMR (400 MHz, MeOD) δ (ppm) 8.64 - 8.60 (m, 1H), 8.34 (d, J = 7.5 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 5.5 Hz, 2H), 7.51 (dd, J = 10.9, 5.5 Hz, 1H), 7.10 (dd, J = 7.9, 4.6 Hz, 1H), 5.22 (s, 2H), 4.18 (s, 1H), 3.31 (s, 3H), 1.12 (s, 6H). HRMS: (ES) C18H21NaN5O2S [M + Na]⁺ 394.1313.

Synthesised via Route 6 1H NMR (400 MHz, MeOD) δ (ppm) 8.56 (dd, J = 4.6, 1.6 Hz, 1H), 8.30 (d, J = 7.7 Hz, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 7.02 (dd, J = 8.0, 4.6 Hz, 1H), 4.82 (s, 2H), 3.30 - 3.27 (m, 1H), 3.04 (s, 3H), 1.14 (d, J = 34.1 Hz, 6H). HRMS: (ES) C18H21NaN5O2S [M + Na]⁺ 394.1311.

Synthesised via Route 6 1H NMR (400 MHz, DMSO) δ (ppm) 8.72 - 8.44 (m, 1H), 8.44 (d, J = 42.8 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 7.9 Hz, 2H), 7.05 (d, J = 35.0 Hz, 1H), 4.74 (d, J = 4.3 Hz, 2H), 4.14 - 3.88 (m, 1H), 1.01 (dd, J = 23.4, 16.7 Hz, 6H). HRMS: (ES) C18H18F3N5Na [M + Na]⁺ 384.1410.

Synthesised via Route 6 1H NMR (400 MHz, MeOD) δ (ppm) 8.76 (s, 1H), 8.64 (s, 1H), 8.39 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.17 (s, 1H), 4.90 (d, J = 2.4 Hz, 2H), 4.18 (d, J = 8.2 Hz, 1H), 1.15 (s, 6H). HRMS: (ES) C17H17F3N6Na [M + Na]⁺ 385.1366.

Synthesised via Route 1 1H NMR (400 MHz, CDCl3) δ (ppm) 7.49 (d, J = 5.3 Hz, 1H), 7.29 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 5.3 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 5.17 (s, 1H), 4.77 (d, J = 7.8 Hz, 1H), 4.70 (d, J = 5.5 Hz, 2H), 4.20 (m, 1H), 3.79 (s, 3H), 1.22 (d, J = 6.5 Hz, 6H). HRMS: (ES) C17H21N4OS [M + H]⁺ 329.1432.

Synthesised via Route 1 1H NMR (400 MHz, CDCl3) δ (ppm) 7.47 (d, J = 5.3 Hz, 1H), 7.34 (dd, J = 7.4, 1.3 Hz, 1H), 7.28 - 7.22 (m, 1H), 7.07 (d, J = 5.3 Hz, 1H), 6.90 (dd, J = 14.2, 7.7 Hz, 2H), 5.42 (s, 1H), 4.82 (d, J = 7.8 Hz, 1H), 4.78 (d, J = 5.8 Hz, 2H), 4.22 (m, 1H), 3.86 (s, 3H), 1.23 (d, J = 6.5 Hz, 6H). HRMS: (ES) C17H21N4OS [M + H]⁺ 329.1434.

Synthesised via Route 1 1H NMR (400 MHz, CDCl3) δ (ppm) 7.52 (d, J = 5.3 Hz, 1H), 7.10 (d, J = 5.3 Hz, 1H), 6.92 (d, J = 4.6 Hz, 2H), 6.86 - 6.81 (m, 1H), 5.05 (s, 1H), 4.83 (s, 1H), 4.71 (d, J = 5.4 Hz, 2H), 4.21 (td, J = 13.1, 6.5 Hz, 1H), 3.87 (d, J = 3.2 Hz, 3H), 3.85 (s, 3H), 1.24 (d, J = 6.5 Hz, 6H). HRMS: (ES) C18H23N4O2S [M + H]⁺ 359.1542.

Synthesised via Route 4 1H NMR (400 MHz, CDCl3) δ (ppm) 9.71 (s, NH), 8.49 (s, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.37 (dd, J = 8.3, 5.5 Hz, 2H), 7.25 (d, J = 5.7 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.87 (t, J = 8.6 Hz, 2H), 4.80 (s, 2H), 4.17 (dd, J = 12.6, 6.3 Hz, 1H), 1.18 (d, J = 6.5 Hz, 6H). HRMS: (ES) C18H20N4 [M + H]⁺ 311.1669.

Synthesised via Route 4 1H NMR (400 MHz, CDCl3) δ (ppm) 8.04 (d, J = 5.6 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.36 (t, J = 7.1 Hz, 2H), 7.19 (d, J = 7.8 Hz, 1H), 7.17 (dd, J = 4.7, 2.8 Hz, 1H), 7.05 - 7.00 (m, 1H), 6.98 (d, J = 10.0 Hz, 1H), 4.86 (d, J = 3.5 Hz, 2H), 4.14 (m, 3H), 1.15 (d, J = 6.7 Hz, 6H). HRMS: (ES) C18H20N4 [M + H]⁺ 311.1669.

Synthesised via Route 4 1H NMR (400 MHz, CDCl3) δ (ppm) 8.09 (d, J = 7.7 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.14 (t, J = 7.5 Hz, 1H), 6.21 - 6.09 (m, 2H), 4.76 (s, 2H), 4.14 (dt, J = 11.4, 5.0 Hz, 1H), 1.19 (d, J = 6.5 Hz, 6H). HRMS: (ES) C18H20CIN4 [M + H]⁺ 327.1373.

Synthesised via Route 4 1H NMR (400 MHz, CDCl3) δ (ppm) 8.19 - 8.13 (m, 1H), 7.58 (td, J = 7.2, 3.2 Hz, 1H), 7.42 (d, J = 7.0 Hz, 1H), 7.37 - 7.27 (m, 3H), 7.21- 7.15 (m, 2H), 4.90 (d, J = 2.3 Hz, 2H), 4.13 (m, 1H), 1.14 (d, J = 6.5 Hz 6H). HRMS: (ES) C18H20CIN4 [M + H]⁺ 327.1374.

Synthesised via Route 4 1H NMR (400 MHz, CDCl3) δ (ppm) 8.29 (s, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 10.2 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.77 (d, J = 8.4 Hz, 2H), 4.78 (d, J = 4.2 Hz, 2H), 4.24 (m, 1H), 3.73 (s, 3H), 1.24 (d, J = 6.5 Hz, 6H). HRMS: (ES) C19H23N4O [M + H]⁺ 323.1869.

Synthesised via Route 4 1H NMR (400 MHz, CDCl3) δ (ppm) 7.87 (d, J = 7.4 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.30 - 7.26 (m, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 6.6 Hz, 1H), 6.85 (d, J = 6.6 Hz, 1H), 4.84 (d, J = 5.0 Hz, 2H), 4.23 (m, 1H), 3.88 (s, 3H), 1.25 (d, J = 6.5 Hz, 6H). HRMS: (ES) C19H23N4O [M + H]⁺ 323.1870.

Synthesised via Route 4 1H NMR (400 MHz, CDCl3) δ (ppm) 8.24 (s, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.27 (d, J = 10.7 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 1.3 Hz, 1H), 6.95 (dd, J = 8.2, 1.4 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 4.77 (s, 2H), 4.25 (dd, J = 11.9, 5.8 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 1.24 (d, J = 6.4 Hz, 6H). HRMS: (ES) C20H25N4O2 [M + H]⁺ 353.1976.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.93-8.67 (m, 2H), 8.48 (d, 1H), 7.75 (d, 1H), 7.62-7.43 (m, 4H), 7.10 (s, 1H), 4.92 (brs, 2H), 3.75-3.30 (m, 5H). LCMS (ES) C₁₈H₁₈N₆F₃ [M+H]⁺ 375.0.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.59 - 8.41 (m, 2H), 7.88 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.61 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.24 (dd, J = 7.5, 4.9 Hz, 1H), 5.00 - 4.77 (m, 2H), 4.26 (dd, J = 12.3, 3.3 Hz, 1H), 3.79 (dd, J = 12.6, 7.3 Hz, 1H), 3.57 - 3.15 (m, 3H), 3.10 (s, 3H). LCMS (ES) C₁₉H₂₀N₆F₃ [M+H]⁺ 389.0.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.83 - 8.41 (m, 3H), 7.76 (d, J = 7.7 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.59 - 7.41 (m, 2H), 7.32 - 6.85 (m, 2H), 5.02 - 4.85 (m, 2H), 2.74 (d, J = 52.1 Hz, 3H). LCMS (ES) C₁₆H₁₅N₅F₃ [M+H]⁺ 334.0.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.41 - 7.91 (m, 4H), 7.78 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 6.6 Hz, 1H), 7.50 (dd, J = 15.9, 8.6 Hz, 2H), 7.30 - 7.08 (m, 1H), 5.05 - 4.84 (m, 2H), 4.80 - 4.67 (m, 2H), 4.57 - 4.47 (m, 1H), 4.46 - 4.18 (m, 2H). LCMS (ES) C₁₈H₁₇N₅F₃O [M+H]⁺ 376.0.

Synthesised via Route 8 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.99-9.00 (d, J=4.0 Hz, 1H), 8.70-8.72 (d, J=8.0 Hz, J=4.0 Hz, 1H),7.74-7.76 (d, J=8.0 Hz, 1H) 7.53-7.60 (m, 3H), 7.43-7.47 (m, 1H), 5.09 (s, 2H), 3.86 (s, 2H), 2.39 (s, 3H).LCMS (ES) C₁₇H₁₇N₅F₃ [M+H]⁺ 348.2.

Synthesised via Route 8 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 9.12 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 8.06 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.51 - 7.48 (dd,J=8.0 Hz,J=4.0 Hz, 1H), 7.45 (t,J=8.0 Hz, 1H), 6.37 (s, 1H), 5.73 (s, 1H), 5.21 (d,J=4.0 Hz, 2H). LCMS (ES) C₁₆H₁₃N₅F₃O [M+H]⁺ 348.0.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.76 - 8.75 (dd, J=4.0 Hz, J=1.6 Hz, 1H), 8.61 - 8.60 (d, J=4.0 Hz, 1H), 7.97 - 7.93 (t, J=8.0 Hz, 2H), 7.47 - 7.44 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.04 -7.01 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 6.40 (s, 0.4H), 5.53 (s, 0.8H), 5.03 - 5.01 (d, J=8.0 Hz, 2H), 3.97 (s, 1H), 3.55 - 3.52 (t, J=8.0 Hz, 2H), 1.78 (s, 2H). LCMS (ES) C₁₇H₁₇N₇F₃ [M+H]⁺ 376.2.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.55 - 8.54 (d, J=4.0 Hz, 1H), 8.47 - 8.43 (m, 2H), 8.34 - 8.32 (d, J=8.0 Hz, 1H), 7.64 - 7.62 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.22 - 7.19 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 4.83 (s, 2H), 4.27 - 4.23 (dd, J=12.0 Hz, J=4.0 Hz, 1H), 3.78 - 3.73 (dd, J=12.0 Hz, J=8.0 Hz, 1H), 3.52 - 3.49 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 3.34 (s, 1H), 3.19 - 3.15 (dd, J=12.0 Hz, J=4.0 Hz, 1H), 3.09 (s, 3H). LCMS (ES) C₁₈H₁₉N₇F₃ [M+H]⁺ 390.0.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.78 - 8.77 (d, J=4.0 Hz, 1H), 8.69 - 8.67 (d, J=8.0 Hz, 1H), 8.62 - 8.61 (d, J=4.0 Hz, 1H), 8.09 - 8.08 (d, J=4.0 Hz, 1H), 7.67 - 7.63 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.52 - 7.49 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 5.14 (s, 2H), 2.90 (s, 2H). LCMS (ES) C₁₅H₁₄N₆F₃ [M+H]⁺ 335.0.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.92 (s, 0.4H), 8.65 -8.61 (m, 2.6H), 8.42 (s, 1H), 7.94 (s, 1H), 7.66 (s, 1H), 7.07 -7.05 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 6.85 - 6.64 (d, 1H), 4.90 (s, 2H), 4.15 (s, 0.5H), 3.76 (s, 0.4H), 1.13 - 0.83 (d, 6H), LCMS (ES) C₁₇H₁₈N₆F₃ [M+H]⁺ 363.0.

Synthesised via Route ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 10.37 (s, 0.87H), 8.76-8.80 (m, 2H), 8.64-8.67 (m, 1H), 8.00-8.08 (m, 2H), 7.66-7.69 (m, 1H), 7.53-7.56 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 4.98-4.99 (d, J=4.0 Hz, 2H), 3.87-3.95 (m, 1H), 2.36-2.38 (d, J=8.0 Hz, 3H), 1.19-1.20 (d, J=4.0 Hz, 1H), 0.96-0.97 (d, J=4.0 Hz, 1H). LCMS (ES) C₁₇H₁₈N₆F₃ [M+H]⁺ 363.2.

Synthesised via Route 4 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 12.06-12.48 (m, 1H), 9.89-10.32 (m, 1H), 8.65 (d, J=4.14 Hz, 1H), 8.34 (brs, 1H), 8.00 (d, J=7.78 Hz, 1H), 7.62-7.90 (m, 3H), 7.41 (brs, 1H), 4.98 (d, J=3.64 Hz, 2H), 3.90 (brs, 1H), 0.96 (brs, 6H). LCMS (ES) C₁₈H₁₉N₅F₃ [M+H]⁺ 362.2.

Synthesised via Route 7 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.49-9.02 (m, 2H), 8.37 (d, J=3.51 Hz, 1H), 7.90 (d, J=8.03 Hz, 1H), 7.51-7.74 (m, 3H), 6.55 (brs, 1H), 4.90 (d,J=4.02 Hz, 2H), 3.59-4.24 (m, 1H), 0.62-1.27 (m, 6H). LCMS (ES) C₁₇H₁₈N₆F₃ [M+H]⁺ 363.2.

Synthesised via Route 1 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.60 (d,J=4.27 Hz, 1H), 8.05(brs, 1H), 7.87-7.95 (m, 2H), 7.67 (dd, J=8.03, 4.64 Hz, 1H), 7.03 (d, J=5.14 Hz, 1H), 6.11 (d, J=7.78 Hz, 1H), 4.85 (d, J=5.14 Hz, 2H), 3.73-4.01 (m, 1H), 0.74-1.16 (m, 6H). LCMS (ES) C₁₆H₁₇N₅F₃S [M+H]⁺ 368.2.

Synthesised via Route 2 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.55 (s, 1H), 8.12-8.13 (d, J=4.0 Hz, 1H), 7.73-7.75 (d, J=8.0 Hz, 1H), 7.57-7.61 (t, J=8.0 Hz, 1H), 7.51-7.53 (d,J=8.0 Hz, 1H), 7.43-7.47 (t, J=8.0 Hz, 1H), 7.36-7.37 (d, J=4.0 Hz, 1H), 4.90-4.91 (d, J=4.0 Hz, 2H), 3.55 (s, 2H), 3.16 (s, 1H), 2.13 (s, 3H). LCMS (ES) C₁₆H₁₆N₄F₃S [M+H]⁺ 353.2.

Synthesised via Route 2 ¹H NMR (400 MHz, MeOD) δ (ppm) 8.08-8.10 (d, J=8.0 Hz, 1H), 7.72-7.74 (d, J=8.0 Hz, 1H), 7.51-7.60 (m, 3H), 7.41-7.45 (d, J=8.0 Hz, 1H), 5.08 (s, 2H). LCMS (ES) C₁₅H₁₂N₄F₃OS [M+H]⁺ 353.0.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.05 - 8.53 (m, 2H), 8.47 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.56 - 7.40 (m, 2H), 7.21- 6.92 (m, 2H), 4.93 (b, 2H), 2.92 - 2.63 (m, 1H), 0.86 - 0.04 (m, 4H). LCMS (ES) C₁₈H₁₇N₅F₃ [M+H]⁺ 360.2.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 10.35 - 9.61 (m, 1H), 9.20 - 8.16 (m, 3H), 7.80 (d, J = 7.7 Hz, 1H), 7.71 - 7.46 (m, 4H), 5.02 (d, J = 26.4 Hz, 2H), 2.94 - 2.59 (m, 1H), 2.33 (s, 3H), 0.98 - 0.37 (m, 4H). LCMS (ES) C₁₈H₁₇N₅F₃ [M+H]⁺ 360.2.

Synthesised via Route 8 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 11.22 (s, 1H), 9.03 (t, J=5.5 Hz, 1H), 8.64 - 8.48 (m, 2H), 7.82 - 7.74 (m, 1H), 7.68 -7.60 (m, 1H), 7.54 - 7.47 (m, 2H), 7.25 (dd, J=4.7, 8.0 Hz, 1H), 4.89 (d, J=5.1 Hz, 2H). LCMS (ES) C₁₅H₁₂N₄F₃O [M+H]⁺ 321.2.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.0 (s, 0.37H), 8.62-8.68 (m, 2.48H), 8.46-8.48 (d, J=8.0 Hz, 1H), 7.94 (s, 1H), 7.80 (s, 0.36H), 7.66 (s, 1H), 7.60 (s, 0.4H), 7.11-7.14 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 4.20-5.08 (m, 7H). LCMS (ES) C₁₇H₁₆N₆F30 [M+H]⁺ 377.2.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.79 - 8.11 (m, 4H), 7.72 (d, J = 7.8 Hz, 1H), 7.42 (dd, J = 7.8, 4.7 Hz, 1H), 7.09 -6.65 (m, 2H), 4.67 (b, 2H), 2.70 - 2.34 (m, 1H), 0.54 - -0.39 (m, 4H). LCMS (ES) C₁₇H₁₆N₆F₃ [M+H]⁺ 361.2.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 10.46 - 9.78 (m, 1H), 9.28 - 8.41 (m, 4H), 8.08 (d, J = 7.8 Hz, 1H), 7.72 (t, J = 9.1 Hz, 1H), 7.64 - 7.49 (m, 1H), 5.03 (d, J = 26.1 Hz, 2H), 2.97 - 2.59 (m, 1H), 2.37 (s, 3H), 1.00 - 0.27 (m, 4H). LCMS (ES) C₁₇H₁₆N₆F₃ [M+H]⁺ 361.2.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.62-8.63 (dd, J=4.0 Hz, 2H), 7.65-8.39 (m, 3H), 6.97-7.00 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 6.75-6.85 (m, 1H), 5.08 (s, 2H), 4.15 (s, 0.45), 3.49-3.67 (m, 2H), 3.27 (s, 1H), 0.81 - 1.15 (d, 6H) LCMS (ES) C₁₈H₂₀N₆F₃ [M+H]⁺ 377.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.61-8.64 (dd, J=4.0 Hz, J=8.0 Hz, 2H), 8.37-8.39 (d, J=8.0 Hz, 1H), 7.82 (bs, 1H), 7.61-7.64 (m, 1H), 7.00-7.03 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 5.06 (s, 2H), 3.54 (s, 3H), 3.33 (s, 1H), 2.78 (s, 3H), 0.84-1.06 (m, 6H). LCMS (ES) C₁₉H₂₂N₆F₃ [M+H]⁺ 391.0.

Synthesised via Route 6 ¹H NMR (400 MHz, MeOD) δ (ppm) 8.65 (dd, J = 4.7, 1.9 Hz, 1H), 8.56 (d, J = 4.4 Hz, 1H), 8.42 (dd, J = 8.0, 1.9 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.58 (dd, J = 8.0, 4.7 Hz, 1H), 7.15 (dd, J = 7.9, 4.7 Hz, 1H), 4.99 (b, 2H), 4.73 -4.43 (m, 1H), 2.93 (s, 3H), 1.01 (b, 6H). LCMS (ES) C₁₈H₂₀N₆F₃ [M+H]⁺ 377.2.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.80 (s, 1H), 8.89 (dd, J = 8.0, 1.7 Hz, 1H), 8.75 (dd, J = 5.2, 1.6 Hz, 1H), 8.65 (d, J = 4.5 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.66 (dd, J = 8.0, 4.6 Hz, 1H), 7.49 (dd, J = 7.9, 5.3 Hz, 1H), 4.99 (d, J = 4.9 Hz, 2H), 4.89 - 4.75 (m, 1H), 3.00 (s, 3H), 2.34 (s, 3H), 1.06 (d, J = 6.5 Hz, 6H). LCMS (ES) C₁₈H₂₀N₆F₃ [M+H]⁺ 377.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.91 (t, J=5.33 Hz, 1 H), 8.68 (dd, J=4.33, 1.69 Hz, 1 H), 8.61 (d, J=4.39 Hz, 1 H), 8.48 (dd, J=8.03, 1.76 Hz, 1 H), 7.99 (d, J=7.91 Hz, 1 H), 7.65 (dd, J=7.97, 4.58 Hz, 1 H), 7.12 (dd, J=7.91, 4.39 Hz, 1 H), 4.86 (d, J=4.77 Hz, 2 H), 3.87 (br. s., 4 H), 2.18 (m, 2 H). LCMS (ES) C₁₇H₁₆N₆F₃ [M+H]⁺ 361.1.

Synthesised via Route 8 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.28 (t, J=5.27 Hz, 1 H), 8.91 (dd, J=4.39, 1.76 Hz, 1 H), 8.59 - 8.72 (m, 2 H), 7.98 (d, J=7.91 Hz, 1 H), 7.66 (dd, J=8.03, 4.64 Hz, 1 H), 7.48 (dd, J=8.16, 4.39 Hz, 1 H), 4.93 (dd, J=5.2 Hz, 2 H), 3.73 (m, 1 H), 1.18 (d, J=6.78 Hz, 6 H). LCMS (ES) C₁₇H₁₇N₅F₃S [M+H]⁺ 379.9.

Synthesised via Route 9 ¹H NMR (400 MHz, MeOD) δ (ppm) 8.70 (d, J=3.3 Hz, 1H), 8.64 (d, J=4.4 Hz, 1H), 8.57 (dd, J=8.2, 1.6 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.65 (dd, J=7.9, 4.8 Hz, 1H), 7.42 (dd, J=8.1, 4.7 Hz, 1H), 5.59 (s, 1H), 4.60 (s, 2H), 3.98-4.19 (m, 1H), 1.22 (d,J=6.0 Hz, 6H). LCMS (ES) C₁₈H₁₉N₅F₃ [M+H]⁺ 362.0.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.66 (m., 1H), 8.47 (m., 2H), 7.57 - 7.68 (m, 2H), 7.50 (t, J=9.03 Hz, 1H), 7.25 (br. s., 1H), 4.98 - 5.10 (m, 2H), 4.30 - 4.67 (m, 1H), 1.29 (d, J=6.53 Hz, 6H). LCMS (ES) C₁₈H₁₈N₅F₄ [M+H]⁺ 380.2.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.57 (dd, J=4.39, 1.76 Hz, 1H), 8.24 - 8.36 (m, 1H), 7.79 - 8.19 (m, 1H), 6.98 (br. s., 1H), 6.56 (br. s., 1H), 4.16 (dd, J=13.68, 6.78 Hz, 1H), 3.43 -3.57 (m, 2H), 3.27 (br. s., 1H), 3.11 (t, J=7.40 Hz, 1H), 2.86 (dt, J=12.05, 7.91 Hz, 1H), 2.61 - 2.68 (m, 1H), 2.33 - 2.39 (m, 1H), 1.93 - 2.06 (m, 1H), 1.67 - 1.85 (m, 5H), 1.15 (d, J=6.53 Hz, 6H). LCMS (ES) C₁₈H₂₆N₆F₃ [M+H]⁺ 383.2.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.61 - 8.68 (m, 2 H), 8.45 (d, J=7.78 Hz, 1 H), 7.91 (br. s., 1 H), 7.66 (dd, J=7.53, 4.89 Hz, 1 H), 7.08 (dd, J=7.91, 4.39 Hz, 1 H), 4.93 (s., 2 H), 1.17 (br. s., 9 H). LCMS (ES) C₁₈H₂₀N₆F₃ [M+H]⁺ 377.0.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.64 (d,J=3.26 Hz, 1H), 8.48 (dd, J=7.97, 1.57 Hz, 1H), 8.44 (m., 1H), 7.57 - 7.68 (m, 2H), 7.45 - 7.54 (m, 1H), 7.17 (dd, J=8.03, 4.77 Hz, 1H), 5.01 (s, 2H), 3.30 (s, 6H). LCMS (ES) C₁₇H₁₆N₅F₃ [M+H]⁺ 366.1.

Synthesised via Route 8 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.18 (t, J=5.5 Hz, 1H), 9.06 (dd, J=1.8, 4.4 Hz, 1H), 8.79 (dd, J=1.8, 8.3 Hz, 1H), 8.64 (d, J=4.5 Hz, 1H), 8.60 (s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.71-7.57 (m, 2H), 4.99 (d, J=5.0 Hz, 2H). LCMS (ES) C₁₄H₁₁N₅F₃ [M+H]⁺ 306.1.

Synthesised via Route 6 ¹H NMR (400 MHz, MeOD) δ (ppm) 8.68 (dd, J=4.64, 1.88 Hz, 1H), 8.57 (d, J=4.52 Hz, 1H), 8.41 (dd, J=7.97, 1.82 Hz, 1H), 8.02 (d, J=8.03 Hz, 1H), 7.60 (dd, J=7.97, 4.71 Hz, 1H), 7.17 (dd, J=8.03, 4.64 Hz, 1H), 4.98 (s, 2H), 3.89 (br. s., 4H), 1.47 (s, 3H). LCMS (ES) C₁₈H₁₈N₆F₃O [M+H]⁺ 391.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.90 (br. s., 1H), 8.68 (br. s., 1H), 8.61 (br. s., 1H), 8.49 (d, J=7.28 Hz, 1H), 7.93 (br. s., 1H), 7.65 (br. s., 1H), 7.13 (br. s., 1H), 4.87 (br. s., 2H), 3.82~4.18 (m, 3H), 2.30 (br. s., 1H), 1.80 (br. s., 1H), 1.15 (m, 3H). LCMS (ES) C₁₈H₁₈N₆F₃ [M+H]⁺ 375.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.55 - 8.78 (m, 3H), 8.47 (d, J=8.03 Hz, 1H), 7.91 (br. s., 1 H), 7.62 (dd, J=7.97, 4.58 Hz, 1H), 7.08 (dd, J=7.78, 4.52 Hz, 1H), 4.92 (br. s., 2H), 3.83 (br. s., 2H), 1.98 - 2.02 (t, J=7.60 Hz, 2H), 1.27 (br. s., 6H). LCMS (ES) C₁₉H₂₀N₆F₃ [M+H]⁺ 389.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.85 (br. s., 1H), 8.54 -8.74 (m, 2H), 8.47 (br. s., 1H), 7.98 (br. s., 1H), 7.64 (br. s., 1H), 7.07 (br. s., 1H), 4.89 (br. s., 2H), 3.46 (s, 2H), 3.22 (s, 2H), 1.82 (br. s., 4H.). LCMS (ES) C₁₈H₁₈N₆F₃ [M+H]⁺ 375.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.86 (br. s., 1H), 8.71 (br. s., 1H), 8.62 (br. s., 1H), 8.50 (d, J=7.15 Hz, 1H), 7.93 (d, J=7.28 Hz, 1H), 7.65 (br. s., 1H), 7.15 (br. s., 1H), 4.95 (br. s., 2H), 2.96 (br. s., 3H), 2.64 (br. s., 1H), 0.34 - 0.62 (m, 4H). LCMS (ES) C₁₈H₁₈N₆F₃ [M+H]⁺ 375.1.

Synthesised via Route 4 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.67 (t, J=5.0 Hz, 1H), 8.58 (d, J=4.3 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.62 (dd, J=8.0, 4.7 Hz, 1H), 7.52 (ddd, J=8.3, 7.0, 1.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.06-7.13 (m, 1H), 4.86 (d, J=4.4 Hz, 2H), 3.30-3.34 (m, 1H), 2.77 (br. s., 3H), 0.88 (br. s., 6 H). LCMS (ES) C₁₉H₂₁N_(s)F₃ [M+H]⁺ 376.2.

Synthesised via Route 8 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.08 - 9.11 (t,J=8.0 Hz, 1H), 8.96 - 8.97 (dd, J=4.0 Hz, 1H), 8.71 - 8.74 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 8.62 - 8.63 (d, J=8.0 Hz, 1H), 8.01 - 8.02 (d, J=4.0 Hz, 1H), 7.65 - 7.68 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.50 - 7.53 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 4.95 - 4.96 (d, J=4.0 Hz, 2H), 2.40 (s, 3H). LCMS (ES) C₁₅H₁₃N₅F₃ [M+H]⁺ 320.1.

Synthesised via Route 8 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.71 (br. s., 1H), 9.10 (d, J=2.89 Hz, 1H), 8.85 (d, J=8.16 Hz, 1H), 8.64 (d, J=4.39 Hz, 1H), 8.06 (d, J=7.91 Hz, 1H), 7.54-7.84 (m, 2H), 4.86-5.06 (m, 2H), 2.87-2.95 (m, 1H), 1.16 (d, J=7.03 Hz, 3H), 0.81 (d, J=6.78 Hz, 3H). LCMS (ES) C₁₇H₁₇N₅F₃OS [M+H]⁺ 396.1.

Synthesised via Route 8 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.92 (t,J=5.40 Hz, 1H), 9.17 (dd, J=4.39, 1.76 Hz, 1H), 8.90 (dd, J=8.34, 1.82 Hz, 1H), 8.65 (d, J=4.39 Hz, 1H), 8.09 (d, J=7.91 Hz, 1H), 7.79 (dd, J=8.28, 4.39 Hz, 1H), 7.65 (dd, J=7.97, 4.71 Hz, 1H), 4.99 (d, J=4.89 Hz, 2H), 3.63-3.72 (m, 1H), 1.08 (d, J=6.90 Hz, 6H). LCMS (ES) C₁₇H₁₇N₅F₃O₂S [M+H]⁺ 412.1.

Synthesised via Route 8 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 11.23 (s, 1H), 9.02-9.05 (t, J=8.0 Hz, 1H), 8.64-8.65 (d, J=4.0 Hz, 1H), 8.57-8.59 (dd, J=4.0 Hz, 1H), 8.49-8.51 (dd, J=8.0 Hz, 1H), 7.96-7.98 (d, J=8.0 Hz, 1H), 7.67-7.70 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.23-7.26 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 4.88-4.89 (d, J=4.0 Hz, 2H). LCMS (ES) C₁₄H₁₁N_(s)F₃O [M+H]⁺ 321.9.

Synthesised via Route 6 ¹H NMR (400 MHz, MeOD) δ (ppm) 8.62 (d,J=3.0 Hz, 1H), 8.25 (br. s., 1H), 7.81 (d, J=7.7 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.43-7.50 (m, 1H), 7.06 (br. s., 1H), 6.11 (t, J=7.4 Hz, 1H), 4.68 (br. s., 2H), 3.73 (br. s., 1H), 2.91-3.06 (m, 1H), 2.33 (br. s., 1H), 0.57-1.20 (m, 6H) LCMS (ES) C₂₀H₂₁N₅F₃ [M+H]⁺ 388.1.

Synthesised via Route 6 ¹H NMR (400 MHz, MeOD) δ (ppm) 8.62 (dd, J=4.6, 1.8 Hz, 1H), 8.28 (d,J=7.4 Hz, 1H), 7.84 (d,J=7.8 Hz, 1H), 7.74 (d,J=7.8 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.42-7.50 (m, 1H), 7.07 (dd, J=8.0, 4.6 Hz, 1H), 6.06 (t, J=7.7 Hz, 1H), 4.84 (br. s., 1H), 4.62-4.71 (m, 1H), 3.34 (br. s., 3H), 2.87-3.01 (m, 2H), 2.30-2.46 (m, 1H), 1.05 (d, J=6.8 Hz, 6H). LCMS (ES) C₂₁H₂₃N₅F₃ [M+H]⁺ 402.2.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.72 (d, J=2.51 Hz, 1H), 8.36 (d, J=7.78 Hz, 1H), 7.64 (m, 2H), 7.37 (t, J=7.59 Hz, 1H), 7.29 (d, J=8.00 Hz, 1H), 7.17 (br. s., 1H), 4.81 (d, J=8.53 Hz, 1H), 3.82 (d, J=12.42 Hz, 2H), 2.97-3.07 (m, 1H), 2.00 (br. s., 2H), 1.91 (d, J=11.80 Hz, 1H), 1.79 (d, J=12.42 Hz, 1H), 1.52-1.71 (m, 2H), 1.11-1.24 (m, 1H), 1.03 (d, J=6.53 Hz, 3H), 0.52 (br. s., 2H). LCMS (ES) C₂₂H₂₅N₅F₃ [M+H]⁺ 416.3.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.75 (br. s., 1H), 8.37 (br. s., 1H), 7.68 (br. s., 1H), 7.09-7.56 (m, 4H), 4.75 (br. s., 2H), 3.85 (br. s., 1H), 3.03 (br. s., 2H), 2.71-2.83 (m, 2H), 1.57-2.07 (m, 6H), 0.42-1.12 (m, 6H). LCMS (ES) C₂₃H₂₇N₅F₃ [M+H]⁺ 430.2.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.72-8.74 (dd, J=4.0 Hz, 1H), 8.38-8.39 (d, J=4.0 Hz, 1H), 7.69-7.71 (d, J=8.0 Hz, 2H), 7.44-7.48 (t, J=8.0 Hz, 1H), 7.36-7.39 (t, J=8.0 Hz, 1H), 7.14-7.17 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 5.03 (s, 2H), 3.77-4.06 (m, 6H), 3.17-3.22 (t, J=8.0 Hz, 1H), 1.04-1.23 (m, 4H), 0.51 (bs, 2H). LCMS (ES) C₂₁H₂₃N₅F₃O [M+H]⁺ 418.2.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.74-8.75 (dd, J=4.0 Hz, 1H), 8.40-8.42 (d, J=8.0 Hz, 1H), 7.72-7.74 (d, J=8.0 Hz, 1H), 7.59-7.61 (d, J=8.0 Hz, 1H), 7.41-7.45 (t, J=8.0 Hz, 1H), 7.35-7.39 (t, J=8.0 Hz, 1H), 7.16-7.19 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 4.94 (bs, 1H), 4.64 (bs, 1H), 4.07-4.12 (t, J=8.0 Hz, 1H), 3.92-3.98 (t, J=12.0 Hz, 2H), 3.81-3.85 (t,J=16.0 Hz, 1H), 3.55-3.60 (t, J=12.0 Hz, 1H), 3.17-3.23 (t, J=12.0 Hz, 1H), 2.77 (bs, 2H), 2.33 (bs, 1H), 1.02 (bs, 4H), 0.5 (bs, 2H). LCMS (ES) C₂₂H₂₅N₅F₃O [M+H]⁺ 432.2.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.69-8.72 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 8.50-8.51 (dd, J=4.0 Hz, 1H), 7.78-7.80 (d, J=8.0 Hz, 1H), 7.53-7.56 (t, J=8.0 Hz, 1H), 7.27-7.31 (t, J=8.0 Hz, 1H), 7.22-7.24 (d, J=8.0 Hz, 1H), 6.89 (bs, 1H), 6.74-6.76 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 4.14-4.23 (m, 3H), 3.58 (m, 2 H), 2.07 (bs, 2H), 1.18-1.20 (d, J=8.0 Hz, 6H). LCMS (ES) C₂₀H₂₂N₆F₃ [M+H]⁺ 403.0.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.69-8.72 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 8.51-8.53 (dd, J=4.0 Hz, 1H), 7.78-7.80 (d, J=8.0 Hz, 1H), 7.52-7.55 (t, J=8.0 Hz, 1H), 7.27-7.31 (t, J=8.0 Hz, 1H), 7.21-7.23 (d, J=8.0 Hz, 1H), 6.76-6.79 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 5.13-5.16 (m, 1H), 4.16 (bs, 2H), 3.58-3.61 (t, J=8.0 Hz, 2 H), 3.02 (s, 3H), 2.07 (bs, 2H), 1.16-1.18 (d, J=8.0 Hz, 6H). LCMS (ES) C₂₁H₂₄N₆F₃ [M+H]⁺ 417.0.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.56 (br. s., 1H), 8.96-9.02 (m, 1H), 8.76 (dd, J=8.16, 1.76 Hz, 1H), 8.65 (d, J=4.27 Hz, 1H), 8.02 (d, J=7.91 Hz, 1H), 7.71-8.00 (m, 1H), 7.67 (dd, J=7.91, 4.64 Hz, 1H), 7.59 (dd, J=8.16, 4.39 Hz, 1H), 4.95 (br. s., 2H). LCMS (ES) C₁₅H₁₁N₅F₅S [M+H]⁺ 388.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.97 (t, J=5.46 Hz, 1H), 8.71 (dd, J=4.39, 1.76 Hz, 1H), 8.62 (d, J=4.14 Hz, 1H), 8.50 (dd, J=8.03, 1.88 Hz, 1H), 7.98 (d, J=8.03 Hz, 1H), 7.66 (dd, J=7.91, 4.64 Hz, 1H), 7.15 (dd, J=8.03, 4.52 Hz, 1H), 4.89 (d, J=4.89 Hz, 2H), 3.44 - 3.69 (m, 8H). LCMS (ES) C₁₈H₁₈N₆F₃O [M+H]⁺ 391.2.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl3) δ (ppm) 8.80 (m, 1H), 8.64 (m, 1H), 7.94 (m, 2H), 7.52 - 7.38 (m, 1H), 7.05 (dd, J = 7.7, 4.3 Hz, 1H), 6.28 (m, 1H), 5.05 (dd, J = 44.6, 14.7 Hz, 2H), 4.86 - 4.67 (m, 1H), 4.51 (d, J = 6.3 Hz, 1H), 3.94 (d, J = 8.4 Hz, 1H), 3.68 (dd, J = 33.8, 11.9 Hz, 2H), 3.48 (t, J = 9.7 Hz, 1H), 3.26 (t, J = 12.0 Hz, 1H), 1.16 (b, 3H). LCMS (ES) C₁₉H₂₀N₆F₃O [M+H]⁺ 405.3.

Synthesised via Route 6 ¹H NMR (400 MHz, MeOD) δ (ppm) 8.87 - 8.85 (m, 1H), 8.67 -8.65 (m, 1H), 8.65 - 8.59 (m, 1H), 8.06 - 8.04 (m, 1H), 7.64-7.63 (m, 1H), 7.48 - 7.45 (m, 1H), 5.05 - 4.89 (m, 2H), 4.61 (b, 1H), 4.32 (d, 1H), 3.91 (d, 1H), 3.70 (d, 1H), 3.59 (dd, 1H), 3.45 (t, 1H), 3.32 - 3.30 (m, 1H), 2.70 (s, 3H), 1.14 (b, 3H). LCMS (ES) C₁₉H₂₀N₆F₃O [M+H]⁺ 405.3.

Synthesised via Route 6 ¹H NMR (400 MHz, MeOD) δ (ppm) 8.72 (dd, J = 4.6, 1.9 Hz, 1H), 8.58 (d, J = 4.3 Hz, 1H), 8.46 (dd, J = 8.0, 1.9 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.60 (dd, J = 8.0, 4.7 Hz, 1H), 7.21 (dd, J = 8.0, 4.6 Hz, 1H), 5.02 (s, 2H), 4.08 - 3.49 (m, 4H), 2.52 - 2.31 (m, 2H). LCMS (ES) C₁₈H₁₆N₆F₅ [M+H]⁺ 411.2.

Synthesised via Route 6 ¹H NMR (400 MHz, MeOD) δ (ppm) 8.87 - 8.68 (m, 2H), 8.63 (d, J = 4.5 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.65 (dd, J = 7.7, 4.6 Hz, 1H), 7.57 - 7.45 (m, 1H), 5.11 (b, 2H), 4.16 - 3.68 (m, 4H), 2.72 (s, 3H), 2.63 - 2.38 (m, 2H). LCMS (ES) C₁₈H₁₆N₆F₅ [M+H]⁺ 411.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.97 (t, J=5.27 Hz, 1H), 8.70 (dd, J=4.39, 1.88 Hz, 1H), 8.61 (d, J=3.89 Hz, 1H), 8.49 (dd, J=7.97, 1.82 Hz, 1H), 7.97 (d, J=7.91 Hz, 1H), 7.65 (dd, J=7.97, 4.58 Hz, 1H), 7.14 (dd,J=7.97, 4.45 Hz, 1H), 4.74 - 4.94 (m, 3H), 3.83 (br. s., 2H), 3.56 (br. s., 2H), 1.71 (br. s., 2H), 1.46 (br. s., 2H). LCMS (ES) C₁₉H₁₉N₆F₄ [M+H]⁺ 407.3.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.01 (t, J=5.52 Hz, 1H), 8.72 (dd, J=4.39, 1.76 Hz, 1H), 8.54 (dd, J=8.03, 1.63 Hz, 1 H), 7.76 (d, J=7.78 Hz, 1H), 7.58-7.63 (m, 1H), 7.51-7.56 (m, 1H), 7.43-7.50 (m, 1H), 7.18 (dd, J=7.97, 4.45 Hz, 1H), 4.88 (d, J=4.89 Hz, 2H), 3.79 (br. s., 4H), 1.78 (br. s., 4H). LCMS (ES) C₂₀H₁₉N₅F₅ [M+H]⁺ 424.3.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.03 (t, J = 5.2 Hz, 1H), 8.78 - 8.69 (m, 1H), 8.62 (d, J = 4.3 Hz, 1H), 8.57 - 8.47 (m, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.65 (dd, J = 7.9, 4.6 Hz, 1H), 7.18 (dd, J = 7.9, 4.4 Hz, 1H), 4.88 (d, J = 4.4 Hz, 2H), 3.91 - 3.64 (m, 4H), 1.99 - 1.61 (m, 4H). LCMS (ES) C₁₉H₁₈N₆F₅ [M+H]⁺ 425.1.

Synthesised via Route 6 ¹H NMR (400 MHz, MeOD) δ (ppm) 8.88 (d, J = 6.6 Hz, 1H), 8.68 (d, J = 4.2 Hz, 1H), 8.63 (d, J = 4.1 Hz, 1H), 8.07 (d, J = 7.7 Hz, 1H), 7.65 (dd, J = 7.9, 4.7 Hz, 1H), 7.49 (dd, J = 7.9, 5.7 Hz, 1H), 5.07 (s, 2H), 4.16 - 3.78 (m, 4H), 2.72 (s, 3H), 2.21 - 1.77 (m, 4H). LCMS (ES) C₁₉H₁₈N₆F₅ [M+H]⁺ 425.0.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.96 (br. s., 1H), 8.69 (dd, J=4.39, 1.76 Hz, 1H), 8.52 (dd, J=8.03, 1.76 Hz, 1H), 7.75 (d, J=7.53 Hz, 1H), 7.56-7.64 (m, 1H), 7.50-7.56 (m, 1H), 7.43-7.50 (m, 1H), 7.14 (dd, J=7.97, 4.45 Hz, 1H), 4.86 (br. s., 2H), 4.32-4.44 (m, 1H), 4.07 (br. s., 2H), 3.40 (m, 2H), 1.91 (br. s., 2H), 1.51 (br. s., 2H). LCMS (ES) C₂₀H₂₀N₅F₃Cl [M+H]⁺ 422.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.99 (t, J=5.27 Hz, 1H), 8.70 (br. s., 1H), 8.61 (d, J=4.39 Hz, 1H), 8.50 (d, J=7.78 Hz, 1H), 7.97 (d, J=8.03 Hz, 1H), 7.65 (dd, J=7.97, 4.58 Hz, 1H), 7.15 (dd, J=7.65, 4.39 Hz, 1H), 4.86 (d, J=4.39 Hz, 2H), 4.38 (m, 1H), 4.04 (br. s., 2H), 3.03 - 3.25 (m, 2H), 1.89 (br. s., 2H), 1.49 (br. s., 2H). LCMS (ES) C₁₉H₁₉N₆F₃Cl [M+H]⁺ 423.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.05 (t, J=5.14 Hz, 1H), 8.72 (d, J=3.14 Hz, 1H), 8.62 (d, J=4.39 Hz, 1H), 8.53 (d, J=6.65 Hz, 1H), 8.01 (d,J=7.78 Hz, 1H), 7.67 (dd,J=7.91, 4.64 Hz, 1H), 7.18 (dd, J=7.91, 4.52 Hz, 1H), 5.29 - 5.51 (m, 1H), 4.87 (d, J=4.77 Hz, 2H), 4.20 (m, 2H), 3.90 (m, 2H). LCMS (ES) C₁₇H₁₆N₆F₄ [M+H]⁺ 379.3.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.12-9.13 (t, J=4.0 Hz, 1H), 8.76-8.77 (dd, J=4.0 Hz, 1H), 8.62-8.63 (d, J=4.0 Hz, 1H), 8.55-8.58 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 8.01-8.02 (d, J=4.0 Hz, 1H), 7.65-7.68 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.23-7.26 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 4.88-4.89 (d, J=4.0 Hz, 2H), 4.25-4.32 (t, J=12.0 Hz, 4H). LCMS (ES) C₁₇H₁₄N₆F₅ [M+H]⁺ 397.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.08 (t, J=5.08 Hz, 1H), 8.74 (dd, J=4.27, 1.63 Hz, 1H), 8.62 (d, J=4.52 Hz, 1H), 8.54 (dd, J=8.09, 1.69 Hz, 1H), 8.01 (d, J=7.78 Hz, 1H), 7.66 (dd, J=7.91, 4.52 Hz, 1H), 7.20 (dd, J=7.97, 4.45 Hz, 1H), 4.88 (d, J=4.64 Hz, 2H), 4.10 (br. s., 2H), 3.84 (br. s., 2H), 3.57 - 3.65 (m, 1H). LCMS (ES) C₁₈H₁₆N₆F₆ [M+H]⁺ 429.0.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.68 (br. s., 1H), 9.06 (dd, J=4.39, 1.76 Hz, 1H), 9.00 (s, 1H), 8.83 (dd, J=8.28, 1.76 Hz, 1H), 8.65 (d, J=4.14 Hz, 1H), 8.27 (s, 1H), 8.16 (d, J=7.91 Hz, 1H), 7.65 (ddd, J=16.94, 8.03, 4.52 Hz, 2H), 5.09 (s, 2H). LCMS (ES) C₁₈H₁₂N₇F₆ [M+H]⁺ 440.0.

Synthesised via Route 10 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 12.61 (s, 1H), 9.78 (s, 1H), 9.24 (s, 1H), 8.92-8.93 (d, J=4.0 Hz, 1H), 8.64-8.68 (m, 2H), 8.13-8.15 (d, J=8.0 Hz, 1H), 7.67-7.70 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.52-7.55 (dd, J=4.0 Hz, J=8.0 Hz, 2H), 7.43-7.47 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.17-7.21 (t, J=8.0 Hz, 2H), 4.99 (s, 2H). LCMS (ES) C₂₁H₁₆N₇F₄O [M+H]⁺ 458.0.

Synthesised via Route 10 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 12.84 (s, 1H), 9.91 (s, 1H), 9.36 (s, 1H), 8.93-8.94 (d, J=4.0 Hz, 1H), 8.64-8.90 (m, 2H), 8.11-8.13 (d, J=8.0 Hz, 1H), 7.57-7.60 (m, 2H), 7.44-7.46 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.37-7.39 (d, J=8.0 Hz, 1H), 7.14-7.16 (d, J=8.0 Hz, 1H), 6.88 (m, 1H), 5.00 (s, 2H). LCMS (ES) C₂₁H₁₆N₇F₄O [M+H]⁺ 458.0.

Synthesised via Route 10 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 12.67 (s, 1H), 9.93 (s, 1H), 9.23-9.26 (t, J=8.0 Hz, 1H), 8.92-8.93 (d, J=4.0 Hz, 1H), 8.64-8.68 (m, 2H), 8.20-8.24 (d, J=8.0 Hz, 1H), 8.12-8.14 (d, J=8.0 Hz, 1H), 7.67-7.70 (dd, J=4.0 Hz,J=8.0 Hz, 1H), 7.43-7.46 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.26-7.31 (t, J=8.0 Hz, 1H), 7.15-7.19 (t, J=8.0 Hz, 1H), 7.07-7.10 (m, 1H), 5.00 (s, 2H). LCMS (ES) C₂₁H₁₆N₇F₄O [M+H]⁺ 458.0.

Synthesised via Route 10 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.64 (t, 1H), 9.22 (s, 1H), 9.16 (bs, 1H), 8.85-8.86 (d, J=4.0 Hz, 1H), 8.61-8.65 (m, 2H), 8.09-8.11 (d, J=8.0 Hz, 1H), 7.66-7.69 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.37-7.40 (dd, J=4.0 Hz, J=8.0 Hz 1H), 4.95 (bs, 2H), 3.18-3.22 (m, 2H), 1.05-1.08 (t, J=8.0 Hz, 3H). LCMS (ES) C₁₇H₁₇N₇F₃O[M+H]⁺ 392.0.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.95 (s, 1H), 8.70 (d, J = 3.0 Hz, 1H), 8.52 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.14 (dd, J = 7.9, 4.4 Hz, 1H), 4.87 (ddd, J = 57.1, 16.1, 4.6 Hz, 2H), 4.51 (b, 1H), 4.25 (d, J = 13.6 Hz, 1H), 3.82 (d, J = 8.9 Hz, 1H), 3.59 (d, J = 11.2 Hz, 1H), 3.45 (d, J = 8.6 Hz, 1H), 3.37 - 3.24 (m, 1H), 3.01 (td, J = 13.0, 3.2 Hz, 1H), 0.91 (b, 3H). LCMS (ES) C₂₀H₂₁N₅F₃O [M+H]⁺ 404.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.98 (s, 1H), 9.01 (d, J = 7.9 Hz, 1H), 8.77 (dd, J = 5.4, 1.2 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.70 - 7.45 (m, 4H), 5.05 - 4.82 (m, 2H), 4.55 (b, 1H), 4.28 (d, J = 13.1 Hz, 1H), 3.89 (d, J = 10.1 Hz, 1H), 3.66 (d, J = 11.3 Hz, 1H), 3.49 (d, J = 10.9 Hz, 1H), 3.34 (d, J = 11.0 Hz, 1H), 3.30 - 3.18 (m, 1H), 2.35 (s, 3H), 1.05 (b, 3H). LCMS (ES) C₂₀H₂₁N₅F₃O [M+H]⁺ 403.9.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.96 (t, J=4.8 Hz, 1H), 8.68 (dd, J=4.4, 1.6 Hz, 1H), 8.52 (dd, J=8.0, 1.6 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.59 (t, J=7.6 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.44 (t, J=7.6 Hz, 1H), 7.13 (dd, J=7.6, 4.4 Hz, 1H), 4.76-4.96 (m, 2H), 4.50 (br s, 1H), 4.24 (d, J=13.2 Hz, 1H), 3.81 (d, J=8.4 Hz, 1H), 3.58 (d, J=11.2 Hz, 1H), 3.42-3.46 (m, 1H), 3.26-3.29 (m, 1H), 2.96-3.03 (m, 1H), 0.91 (s, 3H). LCMS (ES) C₂₀H₂₁N₅F₃O [M+H]⁺ 404.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.99 (t, J = 4.9 Hz, 1H), 8.70 (dd, J = 4.4, 1.7 Hz, 1H), 8.61 (d, J = 4.2 Hz, 1H), 8.51 (dd, J = 8.0, 1.7 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.64 (dd, J = 7.9, 4.7 Hz, 1H), 7.15 (dd, J = 8.0, 4.5 Hz, 1H), 4.87 (ddd, J = 57.3, 16.4, 4.3 Hz, 2H), 4.46 (m, 1H), 4.22 (d, J = 13.1 Hz, 1H), 3.82 (d, J = 8.9 Hz, 1H), 3.58 (d, J = 11.2 Hz, 1H), 3.44 (dd, J = 11.3, 2.7 Hz, 1H), 3.36 - 3.22 (m, 1H), 3.00 (td, J = 13.2, 3.5 Hz, 1H), 0.88 (b, 3H). LCMS (ES) C₁₉H₂₀N₆F₃O [M+H]⁺ 405.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO) δ (ppm) 8.99 (t, J = 4.9 Hz, 1H), 8.70 (dd, J = 4.4, 1.7 Hz, 1H), 8.61 (d, J = 4.2 Hz, 1H), 8.51 (dd, J = 8.0, 1.7 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.64 (dd, J = 7.9, 4.7 Hz, 1H), 7.15 (dd, J = 8.0, 4.5 Hz, 1H), 4.87 (ddd, J = 57.3, 16.4, 4.3 Hz, 2H), 4.46 (m, 1H), 4.22 (d, J = 13.1 Hz, 1H), 3.82 (d, J = 8.9 Hz, 1H), 3.58 (d, J = 11.2 Hz, 1H), 3.44 (dd, J = 11.3, 2.7 Hz, 1H), 3.36 - 3.22 (m, 1H), 3.00 (td, J = 13.2, 3.5 Hz, 1H), 0.88 (b, 3H). LCMS (ES) C₁₉H₂₀N₆F₃O [M+H]⁺ 405.0.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl3) δ (ppm) 8.67 (d,J=3.3 Hz, 1 H), 8.33 (s, 1 H), 7.83 (d, J=7.9 Hz, 1 H), 7.75 (d, J=7.9 Hz, 1 H), 7.63 (t, J=7.7 Hz, 1 H), 7.45-7.52 (m, 1 H), 7.15 (s, 1 H), 6.05 (t, J=7.7 Hz, 1 H), 4.70 (q, J=8.0 Hz, 1 H), 4.19 (s, 1 H), 3.97 (s, 2 H), 3.37 (s, 1 H), 3.17-3.32 (m, 2 H), 2.90-3.02 (m, 1 H), 2.27-2.44 (m, 1 H), 1.81 (s, 2 H), 1.32-1.61 (m, 2 H) LCMS (ES) C₂₂H₂₂N₅F₃Cl [M+H]⁺ 448.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.72 (dd,J=4.3, 1.6 Hz, 1H), 8.26 (s, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.67 (t, J=7.5 Hz, 1H), 7.47-7.54 (m, 1H), 7.13 (dd, J=7.8, 4.4 Hz, 1H), 5.91 (t, J=7.3 Hz, 1H), 4.88 (d, J=3.6 Hz, 1H), 4.65 (q, J=8.2 Hz, 1H), 3.87-3.46 (m, 4H), 2.79-2.92 (m, 1H), 2.19-2.31 (m, 1H), 1.38-1.91 (m, 4H). LCMS (ES) C₂₂H₂₁N₅F₅ [M+H]⁺ 450.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.68-8.69 (m, 1H), 8.22 (m, 1H), 7.82 (dd, J=12.0, 8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.65 (q, J=8.0 Hz, 1H), 7.46-7.51 (m, 1H), 7.07-7.11 (m, 1H), 5.89-5.91 (m, 1H), 4.85 (m, 1H), 4.59-4.65 (m, 1H), 4.11 (s, 2H), 3.74 (d, J=8.0 Hz, 1H), 3.39- 3.51 (m, 2H), 3.22-3.28 (m, 1H), 2.84-2.97 (m, 2H), 2.21-2.27 (m, 1H), 1.07 (d, J=8.0 Hz, 1.7H), 0.58 (br s, 1.3H). LCMS (ES) C₂₂H₂₃N₅F₃O [M+H]⁺ 430.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.72 (dd, J=4.3, 1.6 Hz, 1H), 8.27 (s, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.47-7.54 (m, 1H), 7.13 (dd, J=7.7, 4.3 Hz, 1H), 5.94 (s, 1H), 4.90 (s, 1H), 4.64 (q, J=8.0 Hz, 1H), 3.38-4.04 (m, 4H), 2.86 (dd, J=9.3, 4.4 Hz, 1H), 2.30-2.44 (m, 2H), 2.18-2.29 (m, 1H). LCMS (ES) C₂₁H₁₉N₅F₅ [M+H]⁺ 436.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.73 (dd, J=4.4, 1.6 Hz, 1H), 8.26 (s, 1H), 7.85 (d,J=7.8 Hz, 1H), 7.76 (d,J=7.7 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.46-7.54 (m, 1H), 7.16 (dd, J=7.7, 4.3 Hz, 1H), 5.93 (s, 1H), 4.90 (s, 1H), 4.56-4.72 (m, 1H), 4.05 (s, 1H), 3.80 (s, 1H), 3.57 (s, 3H), 2.79-2.93 (m, 1H), 2.16-2.31 (m, 1H). LCMS (ES) C₂₁H₁₈N₅F₆ [M+H]⁺ 454.1.

Synthesised via Route 6 ¹H NMR (400 MHz, MeOD) δ (ppm) 8.67 (dd, J=4.6, 1.8 Hz, 1 H), 8.62 (dd, J=4.7, 1.2 Hz, 1 H), 8.34 (br d, J=6.9 Hz, 1 H), 8.27 (d, J=8.0 Hz, 1 H), 7.68 (dd, J=8.0, 4.7 Hz, 1 H), 7.15 (dd, J=8.0, 4.6 Hz, 1 H), 6.05 (br t, J=7.9 Hz, 1 H), 4.73 (q, J=8.3 Hz, 1 H), 4.19-4.26 (m, 1 H), 3.99 (br s, 2 H), 3.37 (br s, 1 H), 3.20-3.32 (m, 2 H), 2.94-3.04 (m, 1H), 2.45 (ddt, J=11.2, 9.3, 7.1, 7.1 Hz, 1H), 1.86 (br s, 2 H), 1.35-1.65 (m, 2 H). LCMS (ES) C₂₁H₂₁N₆F₃Cl [M+H]⁺ 449.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.73 (dd, J=4.4, 1.8 Hz, 1H), 8.66 (d, J=3.6 Hz, 1H), 8.18-8.39 (m, 2H), 7.72 (dd, J=7.9, 4.6 Hz, 1H), 7.15 (dd, J=8.0, 4.5 Hz, 1H), 5.91 (t, J=7.5 Hz, 1H), 4.89 (d, J=4.0 Hz, 1H), 4.67 (q, J=8.0 Hz, 1H), 3.56 (s, 4H), 2.79-2.93 (m, 1H), 2.29-2.40 (m, 1H), 1.70 (s, 4H) LCMS (ES) C₂₁H₂₀N₆F₅ [M+H]⁺ 451.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.70 (d, J=4.0 Hz, 1H), 8.64 (s, 1H), 8.24 (t, J=8.0 Hz, 2H), 7.68-7.72 (m, 1H), 7.09-7.13 (m, 1H), 5.90 (t, J=8.0 Hz, 1H), 4.85-4.88 (m, 1H), 4.62-4.67 (m, 1H), 4.07 (m, 2H), 3.74 (d, J=12.0 Hz 1H), 3.38-3.51 (m, 2H), 3.21-3.27 (m, 1H), 2.67-2.74 (m, 2H), 2.31-2.36 (m, 1H), 1.06 (d, J=4.0 Hz, 1.7H), 0.57 (br s, 1.3H) LCMS (ES) C₂₁H₂₂N₆F₃O [M+H]⁺ 431.3.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.73 (dd, J=4.4, 1.7 Hz, 1H), 8.66 (d, J=4.2 Hz, 1H), 8.20-8.34 (m, 2H), 7.72 (dd, J=8.0, 4.6 Hz, 1H), 7.15 (dd, J=8.0, 4.4 Hz, 1H), 5.94 (t, J=7.1 Hz, 1H), 4.84-4.99 (m, 1H), 4.66 (q, J=8.2 Hz, 1H), 3.36-4.06 (m, 4H), 2.88 (dd, J=10.0, 4.6 Hz, 1H), 2.29-2.44 (m, 3H). LCMS (ES) C₂₀H₁₈N₆F₅ [M+H]⁺ 437.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.74 (d, J=2.8 Hz, 1H), 8.65 (d, J=4.0 Hz, 1H), 8.27 (d, J=7.7 Hz, 2H), 7.72 (dd, J=8.0, 4.6 Hz, 1H), 7.17 (dd, J=8.0, 4.6 Hz, 1H), 5.92 (s, 1H), 4.91 (d, J=4.4 Hz, 1H), 4.67 (q, J=8.2 Hz, 1H), 4.03 (s, 1H), 3.77 (s, 1H), 3.56 (s, 3H), 2.87 (d, J=5.40 Hz, 1H), 2.28-2.39 (m, 1H) LCMS (ES) C₂₀H₁₇N₆F₆ [M+H]⁺ 455.1.

Synthesised via Route 11 ¹H NMR (400 MHz, CDCl3) δ (ppm) 9.05 (dd, J=4.3, 1.7 Hz, 1H), 8.09 (dd, J=8.2, 1.7 Hz, 1H), 7.71 (t, J=7.0 Hz, 2H), 7.52 (t, J=7.5 Hz, 1H), 7.35-7.46 (m, 2H), 6.22 (br s, 1H), 5.12 (d, J=4.9 Hz, 2H), 4.00 (br s, 1H), 3.86 (s, 2H), 3.04 (dd, J=12.6, 6.7 Hz, 2H), 2.47-2.64 (m, 2H), 2.05-2.15 (m, 2H), 1.88-2.00 (m, 2H). LCMS (ES) C₂₁H₂₂N₅F₃Cl [M+H]⁺ 436.1.

Synthesised via Route 11 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.04-9.05 (dd, J=4.0, 1.6 Hz 1H), 8.07-8.09 (dd, J=8.0, 1.6 Hz, 1H), 7.70-7.20 (d, J=8.0 Hz, 1H), 7.68-7.66 (d, J=8.0 Hz, 1H), 7.49-7.52 (t, J=8.0 Hz, 1H), 7.37-7.44 (m, 2H), 6.20 (s, 1H), 5.10-5.11 (d, J=4.0 Hz, 2H), 3.89 (s, 2H), 2.81-2.83 (t, J=4.0 Hz, 4H), 1.95-2.05 (m, 4H). LCMS (ES) C₂₁H₂₁N₅F₅ [M+H]⁺ 438.1.

Synthesised via Route 11 ¹H NMR (400 MHz, MeOD) δ (ppm) 9.14-9.16 (t, J=4.0 Hz, 1H), 8.99-9.01 (dd, J=4.0, 1.6 Hz, 1H), 8.77-8.79 (dd, J=8.0, 4.0 Hz, 1H), 7.74-7.76 (d, J=8.0 Hz, 1H), 7.55-7.59 (m, 2H), 7.44-7.51 (m, 2H), 4.95-4.98 (m, 2H), 3.63-3.73 (q, J=12.0 Hz, 2H), 3.44-3.47 (m, 1H), 3.37-3.40 (m, 1H), 3.25-3.31 (m, 1H), 2.89-2.94 (t, J=12.0 Hz, 1H), 2.54-2.57 (m, 1H), 2.39-2.46 (m, 2H), 0.82-0.84 (d, J=8.0 Hz, 3H). LCMS (ES) C₂₁H₂₃N₅F₃O [M+H]⁺ 418.1.

Synthesised via Route 11 ¹H NMR (400 MHz, CDCl3) δ (ppm) 9.05 (dd, J=4.3, 1.8 Hz, 1H), 8.09 (dd, J=8.2, 1.7 Hz, 1H), 7.71 (t, J=7.9 Hz, 2H), 7.53 (t, J=7.5 Hz, 1H), 7.29-7.46 (m, 2H), 6.25 (br s, 1H), 5.11 (d, J=4.5 Hz, 2H), 3.97 (s, 2H), 3.19 (t, J=13.6 Hz, 2H), 3.03 (t, J=7.0 Hz, 2H), 2.29 (m, 2H). LCMS (ES) C₂₀H₁₉N₅F₅ [M+H]⁺ 424.1.

Synthesised via Route 11 ¹H NMR (400 MHz, MeOD) δ (ppm) 9.01-9.04 (dd, J=4.0, 1.6 Hz, 1H), 8.09-8.12 (dd, J=8.0, 1.6 Hz, 1H), 7.69-7.71 (d, J=8.0 Hz, 1H), 7.62-7.64 (d,J=8.0 Hz, 1H), 7.49-7.53 (t,J=8.0 Hz, 1H), 7.40-7.43 (t, J=8.0 Hz, 1H), 7.35-7.38 (dd, J=8.0, 4.0 Hz, 1H), 6.31 (m, 1H), 5.08-5.10 (d, J=8.0 Hz, 2H), 3.87 (s, 2H), 3.69-3.73 (t, J=8.0 Hz, 2H), 3.44-3.48 (t, J=8.0 Hz, 2H), 3.16-3.22 (m, 1H). LCMS (ES) C₂₀H₁₈N₅F₆ [M+H]⁺ 442.1.

Synthesised via Route 11 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.32 (br s, 1H), 9.03 (br d, J=3.1 Hz, 1H), 8.80 (br d, J=8.2 Hz, 1H), 8.63 (d, J=4.3 Hz, 1H), 8.01 (br d, J=7.8 Hz, 1H), 7.65 (br dd, J=4.6, 8.0 Hz, 2H), 4.98 (br d, J=3.8 Hz, 2H), 4.05 (br s, 1H), 3.67 (br s, 2H), 2.79 (br s, 2H), 2.48-2.35 (m, 2H), 2.09-1.56 (m, 4H). LCMS (ES) C₂₀H₂₁N₆F₃Cl [M+H]⁺ 437.0.

Synthesised via Route 11 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.34 (br s, 1H), 9.02 (dd, J=1.6, 4.4 Hz, 1H), 8.78 (dd, J=1.6, 8.2 Hz, 1H), 8.62 (d, J=4.1 Hz, 1H), 8.00 (br d, J=7.9 Hz, 1H), 7.69-7.56 (m, 2H), 4.97 (br d, J=4.8 Hz, 2H), 3.66 (br s, 2H), 2.57 (m, 4H), 1.84 (br s, 4H). LCMS (ES) C₂₀H₂₀N₆F₅ [M+H]⁺ 439.2.

Synthesised via Route 11 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.28 (br s, 1H), 9.02 (dd, J=1.6, 4.3 Hz, 1H), 8.78 (dd, J=1.6, 8.2 Hz, 1H), 8.62 (d, J=4.3 Hz, 1H), 7.98 (br d, J=7.9 Hz, 1H), 7.62 (dt, J=4.5, 8.8 Hz, 2H), 4.97 (br s, 2H), 3.75-3.46 (m, 4H), 2.99 (br s, 1H), 2.66-2.55 (m, 2H), 2.44 (m, 2H), 0.82 (d, J=6.2 Hz, 3H). LCMS (ES) C₂₀H₂₂N₆F₃O [M+H]⁺ 419.1.

Synthesised via Route 11 ¹H NMR (400 MHz, CDCl3) δ (ppm) 9.04 (dd, J=1.6, 4.4 Hz, 1H), 8.63 (d, J=4.3 Hz, 1H), 8.24 (d, J=8.5 Hz, 1H), 8.17 (d, J=7.8 Hz, 1H), 7.47 (dd, J=4.7, 7.8 Hz, 1H), 7.42 (dd, J=4.4, 8.3 Hz, 1H), 6.74 (br s, 1H), 5.14 (br d, J=5.5 Hz, 2H), 3.92 (s, 2H), 3.13 (t, J=13.4 Hz, 2H), 2.98 (t, J=7.0 Hz, 2H), 2.28 (tt, J=7.1, 14.6 Hz, 2H). LCMS (ES) C₁₉H₁₈N₅F₆ [M+H]⁺ 425.1.

Synthesised via Route 11 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.32 (br s, 1H), 9.01 (dd, J=1.9, 4.4 Hz, 1H), 8.81 (dd, J=1.7, 8.2 Hz, 1H), 8.61 (d, J=4.3 Hz, 1H), 7.97 (d, J=7.9 Hz, 1H), 7.66-7.62 (m, 1H), 7.59-7.56 (m, 1H), 4.96 (br d, J=5.0 Hz, 2H), 3.56 (s, 2H), 3.39 (m, 3H), 3.22 (br d, J=5.9 Hz, 2H). LCMS (ES) C₁₉H₁₇N₆F₆ [M+H]⁺ 443.0.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl3) δ (ppm) 8.78 (dd, J=1.7, 4.5 Hz, 1H), 8.63 (d, J=4.3 Hz, 1H), 8.07 (d, J=6.8 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.46 (dd, J=4.7, 8.0 Hz, 1H), 7.06 (dd, J=4.5, 7.9 Hz, 1H), 6.70 (s, 1H), 5.03 (d, J=5.4 Hz, 4H), 3.15-3.04 (m, 1H), 2.90-2.84 (m, 5H), 2.11 (d, J=12.3 Hz, 2H), 1.69 (s, 2H). LCMS (ES) C₂₀H₂₂N₆F₃O₂S [M+H]⁺ 467.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl3) δ (ppm) 8.73 (dd, J=4.4, 1.6 Hz, 1H), 8.60 (d, J=4.4 Hz, 1H) 7.94 (d, J=8.0 Hz, 1H), 7.89 (dd, J=8.0, 1.6 Hz, 1H), 7.43 (dd, J=8.0, 4.8 Hz, 1H), 6.95 (dd, J=7.6, 4.4 Hz, 1H), 6.23 (br s, 1H), 5.02 (d, J=4.8 Hz, 2H), 3.82 (br s, 4H), 1.31 (br s, 4H), 0.96 (s, 6H).LCMS (ES) C₂₁H₂₄N₆F₃ [M+H]⁺ 417.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl3) δ (ppm) 8.78 (dd, J=4.0, 2.0 Hz, 1H), 8.62 (d, J=4.0 Hz, 1H), 7.94 (dd, J=8.0, 2.0 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.46 (dd, J=8.0, 4.0 Hz, 1H), 7.04 (dd, J=8.0, 4.0 Hz, 1H), 6.28 (t, J=8.0 Hz, 1H), 5.02 (d, J=4.0 Hz, 2H), 4.16 (br s, 2H), 3.72 (br s, 2H), 2.82-2.88 (m, 1H) 1.78-1.86 (m, 4H). LCMS (ES) C₂₀H₁₉N₇F₃ [M+H]⁺ 414.0.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl3) δ (ppm) 8.80 (dd, J=4.5, 1.8 Hz, 1H), 8.63 (d, J=4.4 Hz, 1H), 7.84-8.00 (m, 2H), 7.46 (dd, J=7.9, 4.7 Hz, 1H), 7.04 (dd, J=7.9, 4.5 Hz, 1H), 6.19 (t, J=5.3 Hz, 1H), 5.04 (d, J=5.7 Hz, 4H), 2.82 (t, J=12.1 Hz, 2H), 2.19-2.36 (m, 1H), 1.87 (d, J=12.8 Hz, 2H), 1.46 (m, 2H). LCMS (ES) C₂₀H₁₉N₆F₆ [M+H]⁺ 457.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl3) δ (ppm) 8.72-8.84 (m, 1H), 8.58-8.67 (m, 1H), 7.96 (t, J=8.2 Hz, 2H), 7.45 (dd, J=7.4, 4.7 Hz, 1H), 7.02 (dd, J=7.7, 4.4 Hz, 1H), 6.34 (s, 1H), 5.05 (d, J=5.3 Hz, 2H), 3.53-4.04 (m, 4H), 2.99 (dd, J=15.0, 7.5 Hz, 1H), 2.01-2.27 (m, 2H). LCMS (ES) C₁₉H₁₇N₆F₆ [M+H]⁺ 443.0.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl3) δ (ppm) 8.84 (dd, J=4.4, 1.8 Hz, 1H), 8.65 (d, J=4.0 Hz, 1H), 7.95 (m, J=5.3, 2.4 Hz, 2H), 7.43-7.55 (m, 1H), 7.11 (dd, J=8.1, 4.5 Hz, 1H), 6.29 (t, J=5.4 Hz, 1H), 5.03 (d, J=6.0 Hz, 2H), 4.25-4.53 (m, 4H), 3.45-3.58 (m, 1H). LCMS (ES) C₁₈H₁₅N₇F₃ [M+H]⁺ 386.0.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.79 (dd, J=1.9, 4.5 Hz, 1H), 8.63 (d, J=4.3 Hz, 1H), 8.05 (dd, J=1.9, 8.0 Hz, 1H), 7.97 (d, J=7.9 Hz, 1H), 7.47 (dd, J=4.8, 7.9 Hz, 1H), 7.06 (dd, J=4.5, 8.0 Hz, 1H), 6.65 (t, J=5.4 Hz, 1H), 5.06 (d, J=5.3 Hz, 2H), 4.05-3.58 (m, 4H), 3.20 (m, 1H), 2.39-2.26 (m, 2H). LCMS (ES) C₁₉H₁₇N₇F₃ [M+H]⁺ 400.2.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.79 (dd, J=4.5, 1.8 Hz, 1H), 8.63 (br d, J=4.3 Hz, 1H), 7.84-7.97 (m, 2H), 7.45 (dd, J=7.5, 5.0 Hz, 1H), 7.03 (dd, J=7.9, 4.5 Hz, 1H), 6.20 (br s, 1H), 5.03 (d, J=4.8 Hz, 2H), 3.51-4.00 (m, 6H), 0.85-1.27 (m, 6H). LCMS (ES) C₂₀H₂₂N₆F₃O [M+H]⁺ 419.2.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.88 (s, 1H), 8.74 (d, J=4.0 Hz, 1H), 8.61 (d, J=4.0 Hz, 1H), 8.52 (d, J=4.0 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.64 (dd, J=8.0, 4.0 Hz, 1H), 7.19 (dd, J=8.0, 4.0 Hz, 1H), 4.90 (s, 2H), 3.68 (s, 4H), 3.30 (s, 2H), 1.23 (s, 6H). LCMS (ES) C₂₀H₂₂N₆F₃O [M+H]⁺ 419.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.77 (dd,J=4.0, 1.2 Hz, 1H), 8.62 (d, J=4.0 Hz, 1H), 7.90-7.96 (m, 2H), 7.44 (dd, J=8.0, 4.0 Hz, 1H), 7.03 (dd, J=8.0, 4.0 Hz, 1H), 6.33 (br s, 1H), 5.02 (d, J=4.0 Hz, 2H), 4.58 (br s, 2H), 3.89 (dd, J=12.0, 4.0 Hz, 1H), 3.49-3.54 (m, 2H), 3.00 (t, J=12.0 Hz, 1H), 2.63 (t, J=12.0 Hz, 1H), 1.16 (d, J=8.0 Hz, 3H). LCMS (ES) C₁₉H₂₀N₆F₃O [M+H]⁺ 405.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.73 (dd,J=1.8, 4.4 Hz, 1H), 8.59 (d, J=4.3 Hz, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.99 (s, 1H), 7.43 (dd, J=4.7, 7.8 Hz, 1H), 6.99 (dd, J=4.5, 7.9 Hz, 2H), 5.42-5.17 (m, 1H), 5.04 (d, J=5.0 Hz, 2H), 4.14-3.54 (m, 4H), 2.35-2.30 (m, 1H), 2.27-2.25 (m, 1H). LCMS (ES) C₁₈H₁₇N₆F₄ [M+H]⁺ 393.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.77 (dd, J=1.8, 4.5 Hz, 1H), 8.00 (dd, J=1.8, 8.0 Hz, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.57 (d, J=7.3 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.38-7.45 (m, 1H), 7.03 (dd, J=4.5, 8.0 Hz, 1H), 6.47 (t, J=5.6 Hz, 1H), 5.15 (s, 2H), 5.01 (d, J=5.5 Hz, 2H), 3.06-3.10 (m, 1H), 2.84-2.92 (m, 2H), 2.82 (s, 3H), 2.13 (d, J=12.3 Hz, 2H), 1.71 (s, 2H). LCMS (ES) C₂₁H₂₃N₅F₃O₂S [M+H]⁺ 466.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.71 (dd, J=4.4, 2.8 Hz, 1H), 7.83 (dd, J=8.0, 1.6 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.48 (t, J=7.2 Hz, 1H), 7.38 (t, J=7.2 Hz, 1H), 6.92 (dd, J=7.6, 4.4 Hz, 1H), 6.07 (t, J=5.2 Hz, 1H), 4.99 (d, J=5.6 Hz, 2H), 3.88 (s, 4H), 1.35 (s, 4H), 0.97 (s, 6H). LCMS (ES) C₂₂H₂₅N₅F₃ [M+H]⁺ 416.2.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.82 (dd, J=4.5, 1.8 Hz, 1H), 7.89 (dd, J=8.0, 1.7 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.57-7.63 (m, 1H), 7.50-7.56 (m, 1H), 7.39-7.48 (m, 1H), 7.09 (dd, J=8.1, 4.4 Hz, 1H), 6.11 (s, 1H), 5.01 (d, J=5.9 Hz, 2H), 4.35-4.59 (m, 4H), 3.48-3.60 (m, 1H). LCMS (ES) C₁₉H₁₆N₆F₃ [M+H]⁺ 385.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.84 (t, J=5.5 Hz, 1H), 8.74 (dd, J=4.4, 1.7 Hz, 1H), 8.54 (dd, J=8.1, 1.7 Hz, 1H), 7.75 (d, J=7.7 Hz, 1H), 7.56-7.64 (m, 1H), 7.42-7.51 (m, 2H), 7.19 (dd, J=8.0, 4.5 Hz, 1H), 4.91 (d, J=5.0 Hz, 2H), 3.71 (s, 4H), 3.31 (s, 2H), 1.26 (s, 6H). LCMS (ES) C₂₁H₂₃N₅F₃O [M+H]⁺ 418.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.76 (dd, J=4.4, 1.7 Hz, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.45-7.59 (m, 2H), 7.36-7.44 (m, 1H), 7.00 (dd, J=8.0, 4.5 Hz, 1H), 6.16 (br s, 1H), 5.00 (d, J=5.4 Hz, 2H), 3.56-4.02 (m, 6H), 1.11 (br s, 6H). LCMS (ES) C₂₁H₂₃N₅F₃O [M+H]⁺ 418.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.75 (d, J=3.2 Hz, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.55 (d,J=7.6 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 6.90-6.94 (dd, J=8.0, 4.4 Hz, 1H), 6.17 (s, 1H), 4.99 (d, J=4.8 Hz, 2H), 4.68 (br s, 2H), 3.91 (dd, J=11.2, 2.4 Hz, 1H), 3.56 (m, 2H), 3.03 (m, 1H), 2.67 (t, J=12.0 Hz, 1H), 1.18 (d, J=6.0 Hz, 3H). LCMS (ES) C₂₀H₂₁N₅F₃O [M+H]⁺ 404.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.00 (t, J=8.0 Hz, 1H), 8.70 (dd, J=4.0, 2.0 Hz, 1H), 8.59 (d, J=4.0 Hz, 1H), 8.50 (dd, J=8.0, 2.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.0, 4.0 Hz, 1H), 7.16 (dd, J=8.0, 4.0 Hz, 1H), 4.88 (d, J=4.0 Hz, 2H), 4.49-4.71 (m, 2H), 2.81-2.87 (m, 2H), 2.22 (br s, 1H), 1.88 (d, J=8.0 Hz, 1H), 1.45-1.60 (m, 2H), 1.27 (br s, 1H). LCMS (ES) C₂₀H₁₉N₆F₆ [M+H]⁺ 457.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.77 (dd, J=4.0, 2.0 Hz, 1H), 8.61 (d, J=4.0 Hz, 1H),7.94 (dd, J=8.0, 4.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.45 (dd, J=8.0, 4.0 Hz, 1H), 7.02 (dd, J=8.0, 4.0 Hz, 1H), 6.34 (t, J=4.0 Hz, 1H), 5.01-5.02 (m, 4H), 3.16 (t, J=12.0 Hz, 2H), 1.91 (d, J=16.0 Hz, 2H), 1.37 (m, 5H). LCMS (ES) C₂₁H₂₁N₇F₃ [M+H]⁺ 427.9.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.71-8.76 (m, 2H), 8.61 (d, J=4.0 Hz, 1H), 8.49 (dd, J=8.0, 2.0 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.62 (dd, J=8.0, 4.0 Hz, 1H), 7.13 (dd, J=8.0, 4.0 Hz, 1H), 4.92 (s, 2H), 3.92 (d, J=4.0 Hz, 2H), 3.63-3.73 (m, 2H), 2.84-2.89 (m, 1H), 1.90-1.96 (m, 1H), 1.78-1.85 (m, 1H), 1.53-1.59 (m, 1H), 1.44-1.47 (m, 1H). LCMS (ES) C₂₀H₁₉N₇F₃ [M+H]⁺ 413.9.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.95 (s, 1H), 8.68 (d, J = 2.7 Hz, 1H), 8.61 (d, J = 4.2 Hz, 1H), 8.47 (d, J = 6.4 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 7.8, 4.6 Hz, 1H), 7.12 (dd, J = 7.9, 4.4 Hz, 1H), 4.86 (d, J = 3.8 Hz, 2H), 3.75 - 3.51 (m, 4H), 2.41 - 2.26 (m, 4H), 1.57 - 1.25 (m, 4H). LCMS (ES) C₂₂H₂₂N₆F₅ [M+H]⁺ 465.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.88 (s, 1H), 8.86 (d, J = 8.0 Hz, 1H), 8.75 (d, J = 4.9 Hz, 1H), 8.66 (d, J = 4.3 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.69 (dd, J = 8.0, 4.6 Hz, 1H), 7.54 -7.41 (m, 1H), 4.94 (d, J = 5.2 Hz, 2H), 3.86 - 3.53 (m, 4H), 2.41 (t, J = 13.0 Hz, 4H), 2.31 (s, 3H), 1.75 - 1.34 (m, 4H). LCMS (ES) C₂₂H₂₂N₆F₅ [M+H]⁺ 465.3.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.71 (d, J=4.0 Hz, 1H), 8.61 (d, J=4.0 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.86 (d,J=8.0 Hz, 1H), 7.44 (dd, J=8.0, 4.0 Hz, 1H), 6.97 (dd, J=8.0, 4.0 Hz, 1H), 6.71 (s, 1H), 4.88-5.07 (m, 2H), 4.63 (s, 1H), 3.87-3.97 (m, 3H), 3.37-3.57 (m, 3H), 1.48- 1.51 (m, 1H), 0.43-0.7 (m, 1H), 0.06-0.25 (m, 3H). LCMS (ES) C₂₁H₂₂N₆F₃O [M+H]⁺ 431.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.78 (d, J=2.6 Hz, 1H), 8.62 (d, J=3.9 Hz, 1H), 7.92 (t, J=9.0 Hz, 2H), 7.45 (dd, J=7.7, 4.6 Hz, 1H), 7.03 (dd, J=8.0, 4.5 Hz, 1H), 6.27 (s, 1H), 4.48-5.14 (m, 3H), 3.41-4.40 (m, 3H), 2.37-2.81 (m, 2H), 1.18-1.19 (m, J=5.8 Hz, 6H). LCMS (ES) C₂₀H₂₂N₆F₃O [M+H]⁺ 419.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.72 (s, 1H), 8.58 (d, J=4.0 Hz, 1H), 7.89-8.06 (m, 2H), 7.40-7.45 (m, 1H), 6.98 (dd,J=8.0, 4.0 Hz, 1H), 6.56-6.76 (m, 1H), 5.22 (br s, 0.5H), 4.93-5.09 (m, 2H), 4.79 (s, 0.5H), 4.63 (s, 1H), 3.81-3.94 (m, 1H), 3.41-3.69 (m, 3H) 1.86-1.69 (m, 2H). LCMS (ES) C₁₉H₁₈N₆F₃O [M+H]⁺ 402.9.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.01 (s, 1H), 8.69 (dd, J=4.0, 2.0 Hz, 1H), 8.60 (d, J=4.0 Hz, 1H), 8.50 (dd, J=8.0, 2.0 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.64 (dd, J=8.0, 4.0 Hz, 1H), 7.14 (dd, J=8.0, 4.0 Hz, 1H), 4.81 (s, 2H), 3.56-3.64 (m, 6H), 0.01-0.55 (m, 4H). LCMS (ES) C₂₀H₂₀N₆F₃O [M+H]⁺ 416.9.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.81 (d, J=2.8 Hz, 1H), 8.62 (d, J=4.4 Hz, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.48 (dd, J=4.7, 7.8 Hz, 1H), 7.10 (dd, J=4.5, 7.9 Hz, 1H), 6.62-6.52 (m, 1H), 5.11-4.96 (m, 2H), 4.62 -4.56 (m, 3H), 3.94-3.92 (m, 1H), 3.81-3.78 (m, 2H), 3.47-3.42 (m, 1H). LCMS (ES) C₁₉H₁₇N₇F₃O [M+H]⁺ 416.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.76 (dd, J=4.5, 1.8 Hz, 1H), 8.62 (d, J=4.2 Hz, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.89 (dd, J=7.9, 1.7 Hz, 1H), 7.45 (dd, J=7.9, 4.7 Hz, 1H), 6.99 (dd, J=7.9, 4.5 Hz, 1H), 6.20 (t, J=5.6 Hz, 1H), 4.96-5.11 (m, 2H), 4.65-4.90 (m, 2H), 4.20-4.42 (m, 2H), 2.86-3.19 (m, 2H), 1.84 (d, J=10.6 Hz, 2H), 1.66-1.76 (m, 1H), 1.31-1.53 (m, 2H). LCMS (ES) C₂₀H₂₁N₆F₄ [M+H]⁺ 421.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.82 (dd, J=4.3, 1.7 Hz, 1H), 8.62 (d, J=4.3 Hz, 1H), 7.94 (d, J=8.1 Hz, 2H), 7.45 (s, 1H), 7.08 (dd, J=7.9, 4.4 Hz, 1H), 6.25 (s, 1H), 4.79-5.45 (m, 3H), 3.04 (t, J=13.1 Hz, 1H), 2.00-2.11 (m, 1H), 1.64-1.86 (m, 4H), 1.30-1.54 (m, 2H). LCMS (ES) C₂₀H₁₉N₆F₆ [M+H]⁺ 457.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.89 (t, J=5.6 Hz, 1H), 8.66 (dd, J=4.4, 1.9 Hz, 1H), 8.48 (dd, J=8.0, 1.9 Hz, 1H), 7.74 (d, J=7.7 Hz, 1H), 7.55-7.64 (m, 1H), 7.49-7.54 (m, 1H), 7.41-7.48 (m, 1H), 7.10 (dd, J=8.0, 4.5 Hz, 1H), 4.85 (d, J=5.1 Hz, 2H), 3.41-3.77 (m, 4H), 2.35 (t, J=13.1 Hz, 4H), 1.42 (s, 4H). LCMS (ES) C₂₃H₂₃N₅F₅ [M+H]⁺ 464.2.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.94 (s, 1H), 8.69 (dd, J=4.4 Hz, 1H), 8.52 (d, J=8.0 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.56-7.63 (m, 1H), 7.50-7.55 (m, 1H), 7.42-7.49 (m, 1H), 7.14 (dd, J=7.8, 4.6 Hz, 1H), 4.86 (d, J=4.8 Hz, 2H), 4.58 (s, 2H), 2.94 (t, J=12.0 Hz, 2H), 1.77 (d, J=12.0 Hz, 2H), 1.29 (s, 5H). LCMS (ES) C₂₂H₂₂N₆F₃ [M+H]⁺ 427.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.76 (d, J=4.4 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.41 (t, J=7.2 Hz, 1H), 7.02 (dd, J=8.0, 4.4 Hz, 1H), 6.17 (s, 1H), 5.00 (d, J=5.6 Hz, 2H), 4.28 (s, 1H), 4.22-4.26 (m, 1H), 3.74-3.80 (m, 1H), 3.59 (s, 1H), 2.64 (s, 1H), 2.05 (m, 1H), 1.86-1.95 (m, 1H), 1.77-1.80 (m, 1H), 1.54 (m, 1H). LCMS (ES) C₂₁H₂₀N₆F₃ [M+H]⁺ 413.0.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.79 (dd, J=4.5, 1.8 Hz, 1H), 8.62 (d, J=4.4 Hz, 1H), 7.91-8.01 (m, 2H), 7.47 (dd, J=7.8, 4.7 Hz, 1H), 7.05 (dd, J=8.0, 4.5 Hz, 1H), 6.33 (s, 1H), 5.03 (d, J=5.7 Hz, 2H), 3.96-4.29 (m, 2H), 3.73 (m, 2H), 2.91 (s, 3H), 2.32-2.68 (m, 2H). LCMS (ES) C₁₉H₂₀N₆F₃O₂S [M+H]⁺ 453.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.83 (dd, J=1.8, 4.4 Hz, 1H), 8.63 (d, J=4.3 Hz, 1H), 8.04 (dd, J=1.7, 8.1 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.46 (dd, J=4.7, 7.9 Hz, 1H), 7.09 (dd, J=4.5, 7.9 Hz, 1H), 6.48 (t, J=5.7 Hz, 1H), 5.20-4.77 (m, 3H), 4.06-3.64 (m, 2H), 2.24-2.13 (m, 2H), 2.08-1.97 (m, 2H) LCMS (ES) C₁₉H₁₇N₆F₆ [M+H]⁺ 443.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.96 (t, J=5.1 Hz, 1H), 8.69 (dd, J=1.8, 4.5 Hz, 1H), 8.61 (d, J=4.1 Hz, 1H), 8.50 (dd, J=1.9, 8.0 Hz, 1H), 7.99 (s, 1H), 7.65 (dd, J=4.8, 7.4 Hz, 1H), 7.13 (dd, J=4.5, 8.0 Hz, 1H), 4.90-4.77 (m, 3H), 3.82-3.43 (m, 4H), 2.34-2.33 (m, 1H), 2.11 (s, 1H). LCMS (ES) C₁₈H₁₇N₆F₃Cl [M+H]⁺ 409.0.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.73-8.82 (m, 1H), 7.86 (dd, J=8.0, 1.5 Hz, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.51 (t, J=7.5 Hz, 1H), 7.38-7.45 (m, 1H), 7.00 (dd, J=7.9, 4.4 Hz, 1H), 6.05 (s, 1H), 5.03 (br d, J=5.7 Hz, 2H), 3.58-4.14 (m, 4H), 3.01 (dd, J=16.6, 7.9 Hz, 1H), 2.10-2.29 (m, 2H). LCMS (ES) C₂₀H₁₈N₅F₆ [M+H]⁺ 442.0.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.74 (dd, J=4.0, 1.6 Hz, 1H), 7.70-7.88 (m, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.48-7.62 (m, 2H), 7.37 (t, J=5.2 Hz, 1H), 6.97-6.98 (m, 1H), 6.08-6.18 (m, 1H), 5.30 (s, 0.5H), 4.92-5.08 (m, 2.5H), 4.66 (s, 1H), 3.85-3.99 (m, 1H), 3.52-3.77 (m, 3H), 1.90-1.93 (d, J=11.2 Hz, 2H). LCMS (ES) C₂₀H₁₉N₅F₃O [M+H]⁺ 401.9.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.76 (dd, J=4.5, 1.8 Hz, 1H), 7.88 (dd, J=8.1, 1.7 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.46-7.60 (m, 2H), 7.37-7.45 (m, 1H), 7.00 (dd, J=7.9, 4.5 Hz, 1H), 6.11 (t, J=5.6 Hz, 1H), 4.22-5.18 (m, 4H), 3.96-4.08 (m, 1H), 3.27-3.86 (m, 2H), 2.58 (t, J=11.9 Hz, 2H), 1.08-1.24 (m, 6H). LCMS (ES) C₂₁H₂₃N₅F₃O [M+H]⁺ 418.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.68 (dd, J=4.0, 2.0 Hz, 1H), 8.59 (d, J=4.0 Hz, 1H), 8.46 (dd, J=8.0, 2.0 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.62 (dd, J=8.0, 4.0 Hz, 1H), 7.08 (dd, J=8.0, 4.0 Hz, 1H), 4.97 (d, J=16.0 Hz, 1H), 4.82 (d, J=16.0 Hz, 1H), 4.52 (d, J=16.0 Hz, 1H), 4.15 (d, J=12.0 Hz, 1H), 3.84 (d, J=12.0 Hz, 1H), 3.76 (dd, J=12.0, 8.0 Hz, 1H), 3.25-3.31 (m, 2H), 2.98-2.99 (m, 3H), 2.21-2.27 (m, 1H), 0.81-0.83 (d, J=8.0 Hz, 3H), 0.51-0.53 (d, J=8.0 Hz, 3H). LCMS (ES) C₂₁H₂₄N₆F₃O [M+H]⁺ 433.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.03 (t, J=4.0 Hz, 1H), 8.68 (d, J=4.0 Hz, 1H), 8.59 (d, J=4.0 Hz, 1H), 8.49-8.51 (m, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.63 (dd, J=8.0, 4.0 Hz, 1H), 7.12 (dd, J=8.0, 4.0 Hz, 1H), 4.84 (d, J=3.55 Hz, 2H), 4.24-4.29 (m, 2H), 3.56-3.62 (m, 1H), 3.50-3.53 (m, 1H), 3.00-3.09 (m, 2H), 0.98(d, J=4.0 Hz, 3H), 0.91(d, J=4.0 Hz, 3H). LCMS (ES) C₂₀H₂₂N₆F₃O [M+H]⁺ 419.0.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.77 (dd, J=4.0, 2.0 Hz, 1H), 8.60 (d, J=4.0 Hz, 1H), 7.93 (dd, J=8.0, 2.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.43 (dd, J=8.0, 4.0 Hz, 1H), 7.02 (dd, J=8.0, 4.0 Hz, 1H), 6.27 (t, J=4.0 Hz, 1H), 5.11 (dd, J=16.0, 8.0 Hz, 1H), 4.91-4.95 (m, 1H), 4.74 (d, J=4.0 Hz, 1H), 4.23 (dd, J=12.0, 2.0 Hz, 1H), 4.07-4.10 (m, 1H), 3.97 (dd, J=12.0, 4.0 Hz, 1H), 3.48 (dd, J=12.0, 4.0 Hz, 1H), 3.41 (dd, J=12.0, 2.0 Hz, 1H), 1.15 (dd, J=8.0, 4.0 Hz, 6H). LCMS (ES) C₂₀H₂₂N₆F₃O [M+H]⁺ 419.0.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.00 (s, 1H), 8.68 (d, J=4.0 Hz, 1H), 8.60 (d, J=4.0 Hz, 1H), 8.49 (d, J=4.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.63 (dd, J=8.0, 4.0 Hz, 1H), 7.13 (dd, J=8.0, 4.0 Hz, 1H), 4.85 (d, J=4.0 Hz, 2H), 3.51-3.66 (m, 6H), 1.15-1.50 (m, 8H). LCMS (ES) C₂₂H₂₄N₆F₃O [M+H]⁺ 445.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.77 (dd, J = 4.5, 1.8 Hz, 1H), 8.63 (d, J = 3.9 Hz, 1H), 8.02 (dd, J = 8.0, 1.8 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.46 (dd, J = 7.9, 4.7 Hz, 1H), 7.03 (dd, J = 8.0, 4.5 Hz, 1H), 6.57 (t, J = 5.8 Hz, 1H), 5.04 (d, J = 5.6 Hz, 2H), 4.47 (tt, J = 7.7, 3.8 Hz, 1H), 4.35 - 4.04 (m, 2H), 3.79 - 3.48 (m, 2H), 1.99 - 1.77 (m, 2H), 1.80 - 1.58 (m, 2H). LCMS (ES) C₂₀H₁₉N₆F₆O [M+H]⁺ 473.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.95 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.78 (d, J = 4.3 Hz, 1H), 8.67 (d, J = 4.3 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.70 (dd, J = 8.0, 4.6 Hz, 1H), 7.54 (dd, J = 7.9, 5.5 Hz, 1H), 4.95 (d, J = 4.5 Hz, 2H), 4.72 (dd, J = 8.3, 4.0 Hz, 1H), 4.28 - 3.88 (m, 2H), 3.74 - 3.44 (m, 2H), 2.31 (s, 3H), 2.12 - 1.32 (m, 4H). LCMS (ES) C₂₀H₁₉N₆F₆O [M+H]⁺ 473.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.74-8.86 (m, 1H), 8.62 (br d, J=4.6 Hz, 1H), 7.99 (t, J=7.3 Hz, 2H), 7.46 (dd, J=7.8, 4.7 Hz, 1H), 7.05 (dd, J=8.0, 4.5 Hz, 1H), 6.40-6.55 (m, 1H), 5.79-6.19 (m, 1H), 5.02 (d, J=5.8 Hz, 2H), 4.04-4.28 (m, 4H), 2.92-3.16 (m, 1H). LCMS (ES) C₁₈H₁₆N₆F₅ [M+H]⁺ 411.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.99-9.02 (m, 1H), 8.67-8.71 (m, 1H), 8.59 (d, J=4.0 Hz, 1 H), 8.49-8.54 (m, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.63 (dd, J=8.0, 4.0 Hz, 1H), 7.11-7.18 (m, 1H), 4.97-5.02 (m, 1H), 4.74-4.78 (m, 1H), 4.45-4.47 (m, 0.47H), 4.12-4.15 (m, 1.6H), 3.99 (dd, J=12.0, 4.0 Hz, 2H), 3.76-3.78 (m, 0.33H), 3.44-3.56 (m, 1.6H), 3.00-3.05 (m, 1.6H), 1.08 (d, J=4.0 Hz, 4.3H), 0.94 (t, J=4.0 Hz, 1.6H). LCMS (ES) C₂₀H₂₂N₆F₃O [M+H]⁺ 419.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.77 (dd, J=4.4, 1.6 Hz, 1H), 7.89 (dd, J=8.0, 1.8 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.52 (t, J=7.4 Hz, 1H), 7.36-7.46 (m, 1H), 7.02 (dd, J=8.0, 4.5 Hz, 1H), 5.86-6.22 (m, 2H), 5.01 (d, J=5.8 Hz, 2H), 4.11-4.35 (m, 4H), 3.00-3.15 (m, 1H). LCMS (ES) C₁₉H₁₇N₅F₅ [M+H]⁺ 410.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.95 (s, 1H), 8.67-8.71 (m, 1H), 8.53-8.55 (m, 1H), 7.74 (d,J=8.0 Hz, 1H), 7.58 (t,J=8.0 Hz, 1H), 7.42-7.49 (m, 2H), 7.11-7.17 (m, 1H), 5.00 (t, J=16.0 Hz 1H), 4.75 (d,J=16.0 Hz, 1H), 4.51 (m, 0.32H), 4.17-4.18 (m, 1.7H), 3.98-4.04 (m, 2H), 3.78 (dd,J=12.0, 4.0 Hz, 0.25H), 3.55 (dd, J=12.0, 2.0 Hz, 1.57H), 3.02 (d, J=16.0 Hz, 1H), 1.07 (d, J=4.0 Hz, 4.8H), 0.95 (dd, J=16.0, 4.0 Hz, 1.6H). LCMS (ES) C₂₁H₂₃N₅F₃O [M+H]⁺ 418.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.77 (dd,J=4.0, 2.0 Hz, 1H), 8.61 (d, J=4.0 Hz, 1H), 7.96 (d, J=8.0, 4.0 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.45 (dd, J=8.0, 4.0 Hz, 1H), 7.02 (dd, J=8.0, 4.0 Hz, 1H), 6.35 (br s, 1H), 5.00-5.09 (m, 2H), 4.58 (br s, 2H), 3.94 (dd, J=12.0, 2.4 Hz, 1H), 3.47 (t, J=12.0 Hz, 1H), 2.81-3.01 (m, 2H), 2.65 (br s, 1H), 0.85-0.88 (m, 1H), 0.47-0.60 (m, 2H), 0.35-0.39 (m, 1H), 0.19 (br s, 1H). LCMS (ES) C₂₁H₂₂N₆F₃O [M+H]⁺ 430.9.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.74 (dd, J=4.0, 2.0 Hz, 1H), 8.58 (d, J=4.0 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.42 (d, J=4.0 Hz, 1H), 7.01 (dd, J=8.0, 4.0 Hz, 1H), 6.60-6.66 (m, 1H), 4.89-5.12 (m, 2.6H), 4.65 (d, 0.6H), 4.49 (d, 0.6H), 4.21 (d, 0.3H), 3.63-3.71 (m, 2H), 3.35-3.36 (m, 1H), 2.70-2.81 (m, 1H), 1.10- 1.29 (m, 4H), 0.97 (d, J=8.0 Hz, 2H). LCMS (ES) C₂₀H₂₂N₆F₃O [M+H]⁺ 419.0.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.77 (dd, J=4.5, 1.8 Hz, 1H), 8.62 (d, J=3.9 Hz, 1H), 8.00 (dd, J=7.9, 2.0 Hz, 2H), 7.46 (dd, J=7.8, 4.7 Hz, 1H), 7.02 (dd, J=8.0, 4.5 Hz, 1H), 6.49 (s, 1H), 6.06-6.44 (m, 1H), 5.06 (s, 2H), 4.91 (s, 1H), 3.56-4.00 (m, 4H), 2.20 (m, 2H). LCMS (ES) C₁₉H₁₈N₆F₅O [M+H]⁺ 441.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.93 (t, J=4.0 Hz, 1H), 8.68 (dd, J=4.0, 2.0 Hz, 1H), 8.59 (d, J=4.0 Hz, 1H), 8.49 (dd, J=8.0, 2.0 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.62-7.65 (m, 1H), 7.12 (dd, J=8.0, 4.0 Hz, 1H), 6.51-6.94 (m, 1H), 4.82-4.90 (m, 3H), 3.39-3.70 (m, 3H), 3.20-3.29 (m, 1H), 1.99-2.16 (m, 2H). LCMS (ES) C₁₉H₁₈N₆F₅O [M+H]⁺ 441.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.81 (dd, J=1.9, 4.5 Hz, 1H), 8.64 (d, J=3.9 Hz, 1H), 8.04 (dd, J=1.8, 8.0 Hz, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.47 (dd, J=4.8, 7.9 Hz, 1H), 7.08 (dd, J=4.5, 8.0 Hz, 1H), 6.59 (t, J=5.3 Hz, 1H), 5.89-5.61 (m, 1H), 5.13-4.53 (m, 4H), 4.00 (dd, J=2.1, 11.6 Hz, 1H), 3.74-3.51 (m, 2H), 3.12 (t, J=11.5 Hz, 1H), 3.02 (dd, J=10.7, 13.4 Hz, 1H). LCMS (ES) C₁₉H₁₈N₆F₅O [M+H]⁺ 441.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.81 (dd, J=4.5, 1.8 Hz, 1H), 7.98 (dd, J=8.0, 1.7 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.51-7.61 (m, 2H), 7.39-7.47 (m, 1H), 7.09 (dd, J=7.9, 4.0 Hz, 1H), 6.38 (t,J=5.4 Hz, 1H), 4.95-5.09 (m, 2H), 4.61 (t, J=3.7 Hz, 1H), 4.53 (dd, J=13.8, 3.9 Hz, 1H), 4.37 (br s, 1H),3.93-3.99 (m, 1H), 3.75-3.93 (m, 2H), 3.56-3.63 (m, 1H). LCMS (ES) C₂₀H₁₈N₆F₃O [M+H]⁺ 415.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.80 (dd,J=1.7, 4.5 Hz, 1H), 7.96 (dd, J=1.7, 8.1 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.61-7.56 (m, 1H), 7.55-7.48 (m, 1H), 7.46-7.38 (m, 1H), 7.06 (dd,J=4.5, 8.0 Hz, 1H), 6.31 (t,J=5.5 Hz, 1H), 5.92-5.61 (m, 1H), 5.07-4.96 (m, 2H), 4.96-4.59 (m, 2H), 4.02 (dd, J=2.1, 11.4 Hz, 1H), 3.75-3.57 (m, 2H), 3.20-3.10 (m, 1H), 3.09-2.99 (m, 1H), 3.04 (dd, J=10.7, 13.3 Hz, 1H). LCMS (ES) C₂₀H₁₉N₅F₅O [M+H]⁺ 440.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.83 (t, J=5.6 Hz, 1H), 8.70 (d,J=4.0 Hz, 1H), 8.50 (d,J=8.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.61 (t, J=8.0 Hz, 1H), 7.45 (dd, J=16.0, 8.0 Hz 2H), 7.16 (dd, J=8.0, 4.0 Hz, 1H), 4.84 (d, J=4.0 Hz, 2H), 3.67 (s, 2H), 3.50 (s, 2H), 3.26-3.29 (m 2H), 2.26-2.32 (m, 2H), 2.08 (d, J=4.0 Hz, 2H), 1.53-1.58 (m, 2H). LCMS (ES) C₂₂H₂₃N₅F₃O [M+H]⁺ 430.0.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.82 (s, 1H), 8.73 (d, J=2.4 Hz, 1H), 8.53 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.48 (m, 2H), 7.18 (dd, J=8.0, 4.0 Hz, 1H), 4.88 (d,J=4.0 Hz, 2H), 3.66 (s, 4H), 3.32 (s, 2H), 2.27-2.28 (m, 2H), 1.97 (s, 2H), 1.42-1.47 (m, 4H). LCMS (ES) C₂₃H₂₅N₅F₃O [M+H]⁺ 444.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 9.10 (s, 1H), 8.51-8.70 (m, 3H), 7.91 (s, 1H), 7.62 (s, 1H), 7.14 (s, 1H), 4.72-4.92 (m, 2H), 3.48-4.30 (m, 4H), 3.13-3.16 (m, 1H), 2.89-3.06 (m, 1H), 0.84-1.14 (m, 4H), 0.50 (br s, 2H) LCMS (ES) C₂₀H₂₂N₆F₃O [M+H]⁺ 419.0.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.78-8.67 (m, 1H), 8.56 (t, J=3.3 Hz, 1H), 7.90-8.10 (m, 2H), 7.43 (m, 1H), 6.92 (m, 1H), 5.98 t, J=8.1 Hz, 1H), 3.82-5.01 (m, 4H), 3.74-3.76 (m, 1H), 3.16-3.51 (m, 3H), 3.06 (m, 1H), 2.90 (d, J=7.5 Hz, 1H), 2.29-2.43 (m, 1H), 1.13 (m, 3H). LCMS (ES) C₂₁H₂₂N₆F₃O [M+H]⁺ 431.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.64-8.70 (m, 2H), 8.24 (t, J=8.0 Hz, 2H), 7.69-7.73 (m, 1 H), 7.11 (s, 1H), 5.90 (s, 1H), 4.87 (s, 1H), 4.62-4.69 (m, 1H), 4.08 (s, 2H), 3.73 (d, J=12.0 Hz, 1H), 3.39-3.51 (m, 2H), 3.21-3.24 (m, 1H), 2.84-2.97 (m, 2H), 2.33 (m, 1H), 1.06 (d, J=6.4 Hz, 1.7H), 0.56 (br s, 1.3H). LCMS (ES) C₂₁H₂₂N₆F₃O [M+H]⁺ 431.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.73-8.81 (m, 1H), 8.01 (t, J=9.0 Hz, 1H), 7.68-7.81 (m, 2H), 7.55 (q, J=7.7 Hz, 1H), 7.37-7.44 (m, 1H), 6.91-7.00 (m, 1H), 6.07 (t, J=7.8 Hz, 1H), 4.23-4.80 (m, 4H), 3.85 (d, J=8.3 Hz, 1H), 3.33-3.64 (m, 3H), 3.16 (m, 1H), 2.96 (d, J=4.4 Hz, 1H), 2.33-2.46 (m, 1H), 1.23 (d, J=6.8 Hz, 3H). LCMS (ES) C₂₂H₂₃N₅F₃O [M+H]⁺ 430.2.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.75 (s, 1H), 8.00 (t, J=9.7 Hz, 1H), 7.67-7.79 (m, 2H), 7.54 (q, J=7.6 Hz, 1H), 7.36-7.44 (m, 1H), 6.90-6.99 (m, 1H), 6.06 (t, J=7.9 Hz, 1H), 4.12-4.86 (m, 4H), 3.84 (d, J=8.2 Hz, 1H), 3.27-3.65 (m, 3H), 3.14-3.58 (m, 1H), 2.94 (d, J=4.9 Hz, 1H), 2.31-2.44 (m, 1H), 1.22 (d, J=6.8 Hz, 3H). LCMS (ES) C₂₂H₂₃N₅F₃O [M+H]⁺ 430.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.77 (dd, J=1.8, 4.5 Hz, 1H), 8.62 (d, J=3.8 Hz, 1H), 8.01-7.93 (m, 2H), 7.46 (dd, J=4.6, 7.9 Hz, 1H), 7.02 (dd, J=4.5, 7.9 Hz, 1H), 6.60-5.97 (m, 2H), 5.05 (d, J=5.6 Hz, 2H), 4.57-4.11 (m, 3H), 3.59-3.35 (m, 2H), 2.10-1.97 (m, 1H), 1.85-1.73 (m, 2H), 1.54 (br s, 1H). LCMS (ES) C₂₀H₁₉N₆F₅O [M+H]⁺ 455.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.77 (dd, J=4.0, 2.0 Hz, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.03 (dd, J=8.0, 2.0 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.43 (dd, J=8.0, 4.0 Hz, 1H), 7.03 (dd, J=8.0, 4.0 Hz, 1H), 6.56 (t, J=6.0 Hz, 1H), 4.97-5.16 (m, 2H), 4.66 (dd, J=12.0, 4.0 Hz, 2H), 4.11 (d, J=12.0 Hz, 1H), 3.90 (d, J=12.0 Hz, 1H), 3.82 (d, J=12.0 Hz, 1H), 3.67 (d, J=12.0 Hz, 1H), 3.23 (q, J=8.0 Hz, 1H), 1.87 (d, J=8.0 Hz, 1H). LCMS (ES) C₁₉H₁₈N₆F₃O [M+H]⁺ 403.0.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.78 (d, J=3.1 Hz, 1H), 8.60 (d, J=3.5 Hz, 1H), 7.87-8.14 (m, 2H), 7.39-7.49 (m, 1H), 7.04 (dd, J=7.3, 4.3 Hz, 1H), 6.61 (s, 1H), 4.95-5.22 (m, 2H), 2.88-3.80 (m, 6H), 0.36-1.09 (m, 2H). LCMS (ES) C₁₉H₁₈N₆F₃O [M+H]⁺ 403.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.89 (dd, J=4.5, 1.8 Hz, 1H), 8.66 (d, J=4.4 Hz, 1H), 7.99 (dd, J=8.2, 1.8 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.48 (dd, J=7.8, 4.6 Hz, 1H), 7.19 (dd, J=8.1, 4.5 Hz, 1H), 6.33 (t, J=5.7 Hz, 1H), 5.07 (d, J=5.7 Hz, 2H), 4.39 (br s, 4H). LCMS (ES) C₁₈H₁₄N₆F₇O [M+H]⁺ 463.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.79 (dd, J=4.4, 1.7 Hz, 1H), 8.61 (d, J=4.3 Hz, 1H), 7.96 (d, J=7.8 Hz, 2H), 7.44 (dd, J=7.9, 4.6 Hz, 1H), 7.00-7.11 (m, 1H), 6.23 (br s, 1H), 5.09 (s, 2H), 3.59-4.20 (m, 2H), 1.70-1.75 (m, 2H), 1.31-1.53 (m, 4H), 0.48-0.97 (m, 4H). LCMS (ES) C₂₁H₂₂N₆F₃ [M+H]⁺ 415.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.78 (dd, J=4.5, 1.8 Hz, 1H), 8.62 (d, J=4.0 Hz, 1H), 7.91-8.02 (m, 2H), 7.46 (dd, J=7.5, 4.8 Hz, 1H), 7.03 (dd, J=8.0, 4.5 Hz, 1H), 6.30 (t, J=5.5 Hz, 1H), 4.86-5.11 (m, 3H), 3.50-4.16 (m, 4H), 2.11-2.37 (m, 2H). LCMS (ES) C₁₉H₁₇N₆F₆O [M+H]⁺ 459.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.70 (dd, J=4.4, 2.0 Hz, 1H), 8.62 (d, J=3.9 Hz, 1H), 8.51 (t, J=5.3 Hz, 1H), 8.46 (dd, J=8.0, 1.9 Hz, 1H), 7.95 (d, J=7.4 Hz, 1H), 7.64 (dd, J=8.0, 4.6 Hz, 1H), 7.09 (dd, J=8.0, 4.5 Hz, 1H), 5.02 (d, J=5.0 Hz, 2H), 3.53 (t, J=6.6 Hz, 2H), 3.27 (d, J=8.9 Hz, 2H), 2.10-2.14 (m, 2H), 1.47-1.73 (m, 6H). LCMS (ES) C₂₁H₂₂N₆F₃O [M+H]⁺ 415.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.79 (dd, J=4.5, 1.8 Hz, 1H), 8.63 (d, J=4.0 Hz, 1H), 7.92 (t, J=6.9 Hz, 2H), 7.45 (dd, J=7.9, 4.6 Hz, 1H), 7.04 (dd, J=8.0, 4.5 Hz, 1H), 6.19 (s, 1H), 4.99-5.15 (m, 2H), 4.12-4.55 (m, 3H), 3.46-3.79 (m, 2H), 2.06 (d, J=4.0 Hz, 1H), 1.76-1.93 (m, 2H), 1.50-1.57 (m, 1H). LCMS (ES) C₂₀H₁₉N₆F₆O [M+H]⁺ 473.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.79 (d, J = 3.2 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.02 (dd, J = 7.8, 4.4 Hz, 1H), 6.26 (b, 1H), 5.07 (dt, J = 15.7, 10.4 Hz, 2H), 4.72 (b, 2H), 4.20 (d, J = 13.6 Hz, 1H), 3.97 (t, J = 13.2 Hz, 2H), 3.81 (d, J = 13.2 Hz, 1H), 3.25 (dd, J = 14.4, 6.8 Hz, 1H), 1.94 (d, J = 8.7 Hz, 1H). LCMS (ES) C₂₀H₁₉N₅F₃O [M+H]⁺ 402.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.79 (d, J=2.9 Hz, 1H), 7.87-7.96 (m, 1H), 7.56-7.74 (m, 2H), 7.50 (t, J=7.5 Hz, 1H), 7.36-7.44 (m, 1H), 7.03 (dd, J=7.9, 4.4 Hz, 1H), 6.12 (s, 1H), 4.98-5.25 (m, 2H), 3.52-3.89 (m, 5H), 3.01-3.38 (m, 1H), 0.50-1.17 (m, 2H). LCMS (ES) C₂₀H₁₉N₅F₃O [M+H]⁺ 402.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.98-9.03 (m, 1H), 8.67-8.68 (m, 1H), 8.49-8.56 (m, 1.4H), 7.73 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.42-7.49 (m, 2H), 7.11-7.17 (m, 1H), 4.86 (s 2H), 4.41 (s, 1.4H), 4.17- 4.18 (m, 0.4H), 3.98-4.04 (m, 0.4H), 3.53-3.66 (m, 1.3H), 3.43-3.62 (m, 2.0H), 3.01 (s, 0.5H), 0.93-1.23 (m, 6.0H). LCMS (ES) C₂₁H₂₃N₅F₃O [M+H]⁺ 418.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.97 (s, 1H), 8.75-8.74 (d, J=2.8 Hz, 1H), 8.61-8.60 (d, J=4.4 Hz, 2H), 8.45-8.42 (dd, J=8.8, 3.2 Hz 1H), 7.98-7.96 (d, J=7.6 Hz, 1H), 7.66-7.63 (dd, J=8.0, 4.4 Hz 1H), 4.95-4.91 (d, J=16.4 Hz, 1H), 4.82-4.78 (d, J=16.4 Hz, 1H), 4.43 (br s, 1H), 4.20-4.17 (d, J=13.2 Hz, 1H), 3.83-3.80 (d, J=11.2 Hz, 1H), 3.59-3.56 (d, J=11.2 Hz, 1H), 3.29-3.26 (m, 1H), 2.99-2.95 (m, 1H), 0.87 (s, 3H). LCMS (ES) C₁₉H₁₉N₅F₄O [M+H]⁺ 423.0.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.63 (d, J=3.1 Hz, 2H), 7.93 (d, J=7.9 Hz, 1H), 7.46 (d, J=7.9 Hz, 1H), 7.31 (d, J=3.1 Hz, 1H), 6.21-6.18 (m, 1H), 5.14-4.96 (m, 2H), 4.70 (s, 1H), 4.43 (d, J=13.1 Hz, 1H), 4.56-4.41 (m, 1H), 3.95-3.90 (m, 4H), 3.73-3.70 (m, 1H), 3.52-3.45 (m, 1H), 3.27-3.20 (m, 1H), 1.13 (d, J=6.7 Hz, 3H). LCMS (ES) C₂₀H₂₂N₆F₃O [M+H]⁺ 435.2.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.61 (d, J=4.3 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.44 (dd, J=7.9, 4.6 Hz, 1H), 6.53 (d, J=8.7 Hz, 1H), 5.89 (t, J=5.6 Hz, 1H), 5.03-5.12 (m, 1H), 4.87-4.97 (m, 1H), 4.69 (s, 1H), 4.49 (d, J=13.1 Hz, 1H), 4.08 (s, 3H), 3.92 (dd, J=11.1, 3.3 Hz, 1H), 3.58-3.74 (m, 2H), 3.47 (m, 1H), 3.25 (m, 1H), 1.10 (d, J=6.5 Hz, 3H). LCMS (ES) C₂₀H₂₂N₆F₃O [M+H]⁺ 435.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 9.05 (s, 1H), 9.00 (s, 1H), 8.64 (d, J=4.5 Hz, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.43-7.54 (m, 1H), 6.55-6.89 (m, 1H), 4.29-5.21 (m, 4H), 3.92 (d, J=10.3 Hz, 1H), 3.65-3.76 (m, 1H), 3.36-3.63 (m, 2H), 3.18-3.32 (m, 1H), 1.01-1.35 (m, 3H). LCMS (ES) C₁₈H₁₉N₇F₃O [M+H]⁺ 406.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 9.04 (s, 1H), 8.92 (s, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.49-7.58 (m, 2H), 7.40-7.48 (m, 1H), 6.33-6.57 (m, 1H), 4.42-5.18 (m, 4H), 3.95 (dd, J=11.2, 3.2 Hz, 1H), 3.59-3.77 (m, 2H), 3.41-3.55 (m, 1H), 3.30 (t, J=13.1 Hz, 1H), 1.13-1.38 (m, 3H).LCMS (ES) C₁₉H₂₀N₆F₃O [M+H]⁺ 405.2.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.52-8.67 (m, 2H), 7.85-8.03 (m, 2H), 7.44 (dd, J=7.8, 4.7 Hz, 1H), 6.49 (d, J=5.5 Hz, 1H), 4.89-5.11 (m, 2H), 4.37-4.86 (m, 2H), 4.06 (s, 3H), 3.91 (br dd, J=11.4, 3.2 Hz, 1H), 3.58-3.72 (m, 2H), 3.46 (m, 1H), 3.15-3.30 (m, 1H), 1.12 (br s, 3H). LCMS (ES) C₂₀H₂₂N₆F₃O₂ [M+H]⁺ 435.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.59 (d,J=4.14 Hz, 1H), 8.55 (t, J=5.33 Hz, 1H), 7.92 (d, J=7.91 Hz, 1H), 7.89 (s, 1H), 7.64 (dd, J=7.97, 4.71 Hz, 1H), 4.88 - 4.98 (m, 1H), 4.71-4.82 (m, 1H), 4.38 (s, 1 H), 4.11 (d, J=12.42 Hz, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.78 (dd, J=11.11, 2.95 Hz, 1H) 3.52-3.58 (m, 1 H), 3.42 (dd, J=11.36, 2.95 Hz, 1H), 3.27 (m, 1H), 2.94 (m, 1H), 0.82 (d, J=6.15 Hz, 3H). LCMS (ES) C₂₁H₂₄N₆F₃O₃ [M+H]⁺ 465.2.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.73 (d, J=2.0 Hz, 1H), 8.64 (d, J=4.0 Hz, 1H), 8.23 (d, J=2.1 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.47 (dd, J=8.0, 4.7 Hz, 1H), 7.36 (s, 1H), 4.93-5.16 (m, 2H), 4.34-4.93 (m, 2H), 3.96 (dd, J=11.2, 3.3 Hz, 1H), 3.71-3.79 (m, 1H), 3.61-3.69 (m, 1H), 3.50 (, J=11.9 Hz, 1H), 3.29 (t, J=13.1 Hz, 1H), 1.24 (d, J=16.7 Hz, 3H). LCMS (ES) C₁₈H₁₉N₇F₃O [M+H]⁺ 406.1.

Synthesised via Route 6 ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.70 (d, J=2.1 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.56-7.61 (m, 1H), 7.52 (t, J=7.4 Hz, 1H), 7.38-7.44 (m, 1H), 7.29 (s, 1H), 4.83-5.11 (m, 3H), 4.62 (d, J=13.6 Hz, 1H), 3.97 (dd, J=11.3, 3.5 Hz, 1H), 3.73-3.79 (m, 1H), 3.65-3.71 (m, 1H), 3.53 (t, J=11.8 Hz, 1H), 3.32 (t, J=13.1 Hz, 1H), 1.26 (s, 3H). LCMS (ES) C₁₉H₂₀N₆F₃O [M+H]⁺ 405.1.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) δ 8.92 (t, J = 5.3 Hz, 1H), 8.66 (dd, J = 4.4, 1.8 Hz, 1H), 8.60 (d, J = 4.3 Hz, 1H), 8.47 (dd, J = 8.0, 1.9 Hz, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.63 (dd, J = 8.0, 4.6 Hz, 1H), 7.10 (dd, J = 7.9, 4.5 Hz, 1H), 4.86 (s, 2H), 4.46 (br. s, 2H), 2.70 (br. s, 1H), 2.36 (t, J = 11.3 Hz, 1H), 1.67 (d, J = 10.0 Hz, 1H), 1.49 (br. s, 1H), 1.23 (br. s, 2H), 1.12 -0.96 (m, 1H), 0.71 (s, 3H). HRMS (ES) C₂₀H₂₂F₃N₆ [M+H]⁺ 403.1844.

Synthesised via Route 6 ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 8.92 (t, J= 5.4 Hz, 1H), 8.66 (dd, J = 4.4, 1.6 Hz, 1H), 8.60 (d, J = 4.4 Hz, 1H), 8.47 (dd, J = 8.0, 1.7 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.64 (dd, J = 8.0, 4.6 Hz, 1H), 7.10 (dd, J = 7.9, 4.5 Hz, 1H), 4.86 (d, J = 4.5 Hz, 2H), 4.52 (br. s, 2H), 2.69 (t, J = 12.1 Hz, 2H), 1.70 - 1.37 (m, 3H), 0.83 (m, 5H). HRMS (ES) C₂₀H₂₂F₃N₆ [M+H]⁺ 403.1853.

Biology In Vitro Insect Cell Line Assay

A C6/36 Aedes albopictus cell line infected with Wolbachia pipientis (Wolbachia strain wAlbB) derived from Aa23 A. albopictus cell line (O′Neill et al., 1997; Insect Mol Biol; Turner et al., (2006) J. Immunol. 7:1240-1249) was used to screen compounds. Cells were cultured in Leibovitz’s L15 + L-glutamine supplemented with heat-inactivated Foetal Calf Serum (HI-FCS), non-essential amino acids and tryptose phosphate broth. Culture medium was filter-sterilized through a 0.2 µm filter and stored at 4° C. Compounds were provided as 10 mM stocks in DMSO, diluted to 50 µM working stock to give final concentration of 5 µM on the test plate. Concentrated stocks were frozen at -20° C.

Prior to use in the screening assay, cell cultures were sub-passaged (6 days prior) to provide ~90% confluent cells on Day 0 of screening assay. On Day 0 (assay set-up), the medium was removed from the stock culture flask and replaced with fresh medium. The cells were detached by scraping and cell density was calculated using an automated cell counter. The cells were then diluted at working density and aliquoted at 90 µl to each well of a Cell Carrier 384 well plate (Perkin Elmer). Cell plates were incubated at 26° C.

Control solution (DMSO-medium) was dispensed at 10 µl per well for “untreated” wells. Test solution (Drug-DMSO) was also dispensed at 10 µl (from working plate) per well for “treated” wells. The plates were incubated at 26° C., inside plastic wallet in incubator, for 7 days.

On Day 7, 25 µl of staining medium/dye (SYTO 11, Life Technologies) was added to each sample well and allowed to stain for 15 minutes in the dark. All the medium was removed from each sample well without disturbing the cells and replaced with 100 µl of fresh medium. Plates were imaged on the Operetta High Content Imaging system (Perkin Elmer) and analyzed using texture analysis through Harmony software (Perkin Elmer). The cell-based screen and analysis are described in detail in Clare et al. (2014) J Biomol Screen.

Anti-Wolbachia activity is catagorised in Table 2 as follows +: 1,000 nM < EC₅₀ ≤ 100,000 nM; ++: 100 nM < EC₅₀ ≤ 1,000 nM; +++: 10 nM < EC₅₀ ≤ 100 nM; ++++: 1 nM < EC₅₀ ≤ 10 nM; +++++: 0.01 nM < EC₅₀ ≤ 1 nM; ++++++: EC₅₀ ≤ 0.01 nM.

TABLE 2 Entry Structure In vitro anti-Wolbachia activity 1

+ 2

+ 3

+ 4

++ 5

++++ 6

+ 7

++ 8

++ 9

++ 10

+ 11

++ 12

+ 13

+ 14

++ 15

++ 16

+ 17

+++ 18

+ 19

+ 20

+ 21

+++ 22

+ 23

+++ 24

++ 25

++ 26

++ 27

+ 28

+++ 29

++ 30

++ 31

+ 32

+ 33

++ 34

+ 35

++ 36

+ 37

+ 38

+ 39

+ 40

+ 41

+++ 42

++ 43

++ 44

+++ 45

++ 46

+++ 47

+ 48

++ 49

++++ 50

+++ 51

+++ 52

+++ 53

++++ 54

++++ 55

+++ 56

+++ 57

+++ 58

++ 59

++ 60

+++ 61

+ 62

+++ 63

+++ 64

++ 65

+++ 66

++++ 67

++ 68

+++ 69

+ 70

+ 71

+++ 72

+++ 73

++ 74

+ 75

++ 76

+ 77

++ 78

+ 79

++ 80

+++ 81

+ 82

+ 83

+ 84

+ 85

++ 86

+ 87

++ 88

+ 89

+ 90

+ 91

+ 92

+ 93

++ 94

+ 95

+ 96

+ 97

++ 98

+ 99

+ 101

+ 102

+ 103

+++ 104

++ 105

+ 106

+ 108

+ 109

+ 110

+ 111 + 112

++ 113

+ 114

++ 115

+ 116

++ 117

++ 118

+ 119

++ 120

++ 121

+ 122

+ 123

+ 124

+ 125

+ 126

++ 127

++ 128

++ 129

++ 130

+ 131

+ 132

+ 133

+ 134

+ 135

+ 136

+ 137

+ 138

+ 139

++ 140

++ 141

++ 142

+ 143

+++ 144

+++ 145

+ 146

+ 147

+ 148

+ 149

++ 150

+++ 151

++ 152

++ 153

+++ 154

+ 155

+ 156

++++ 157

+ 158

++ 159

++++ 160

+++ 161

++++ 162

+++++ 163

+++ 164

++++ 165

+++ 166

++ 167

+ 168 ++++ 169

++ 170

+ 171

++ 172

+++++ 173

++++ 174

+++++ 175

++++ 176

++ 177

+ 178

+ 179

+++ 180

+ 181

+ 182

+ 183

++++ 184

+++++ 185

+ 186

+ 187

+ 188

+ 189

+ 190

++ 191

++ 192

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++++ 194

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++++ 196

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++++ 198

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++++ 200

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++++ 203

++ 204

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+++ 206

++ 207

++ 208

++++++ 209

+++ 210

++++ 211

+++ 212

++ 213

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++ 217

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++++ 220

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++++ 222

+ 223

++ 224

+ 225

+ 226

++ 227

++ 228

++ 229

+ 230

+ 231

++ 232

++ 233

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++++ 235

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++ 238

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++++ 243

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++++ 252

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++++ 254

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++++ 256

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++++ 261

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++ 264

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++++ 267

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++++ 275

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+++++ 292

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++++++ 297

++++++ 298

++++++ 299

++++++ 300

++++++ 301

+++++ 302

++++++ 303

++ 304

+ 305

+ 306

+ 307

+ 308

+ 309

++ 310

++ 311

+++++ 312

+++++

In Vitro Microfilariae (Mf) Brugia Malayi Screen

An in vitro microfilariae (Mf) assay was used to screen against Wolbachia of the target parasite, Brugia malayi. The Mf were obtained by peritoneal lavage of gerbils (Meriones unguiculatus) harbouring a patent infection of Brugia malayi as described previously (Griffiths et al., 2010, Lab Animal).

Mf were purified using a PD-10 desalting column (Fisher) followed by centrifugation (1200 rpm for 5 minutes at room temperature) then re-suspended in filter-sterilised culture medium consisting of RPMI supplemented with heat-inactivated Foetal Calf Serum (HI-FCS), 1% Penicillin-Streptomycin and 1% Amphotericin B.

After determining the concentration of Mf, the stock solution was diluted in culture medium to ensure a final concentration of 8000 Mf/well of a 96 well plate (100 µl per well). Compounds to be tested (10 mM stock in 100% DMSO) were diluted to appropriate working concentrations in culture medium and 100 µl was added to the appropriate wells of the 96 well plate containing the Mf. Five replicates were used for each compound and each plate contained doxycycline (5 µM) and vehicle (DMSO) controls. The plates were incubated at 37° C., 5% CO₂, for 6 days.

On day 6, a visual assessment of motility was performed and wells scored from 0 to 4 (where 0 = no movement and 4 = highly motile) in order to assess whether there were any direct effects against the Mf. To perform the anti-Wolbachia readout, DNA was extracted from each individual well using the QIAmp DNA Mini Kit (Qiagen) ‘DNA Purification from Tissues’ protocol.

The number of Wolbachia present in Mf was assessed by quantification of the Wolbachia surface protein (wsp) gene copy number and normalised to the nematode glutathione S-transferase (gst) gene by qPCR based on methods described by McGarry et al., 2004, Mol Biochem Parasitol. DNA samples were amplified in duplicate in the following 20 µl reactions containing 1x QuantiTect SYBR Green PCR master mix (Qiagen): for wsp, 0.3 µM each of forward (CCCTGCAAAGGCACAAGTTATTG) and reverse (CGAGCTCCAGCAAAGAGTTTAATTT) primer, 3 mM MgCl₂ and 2 µl of DNA. For gst, 0.35 µM of forward (GAGACATCTTGCTCGCAAAC) and reverse primer (ATCACGGACGCCTTCACAG), 3.5 mM MgCl₂ and 1 µl of DNA. qPCR was performed using the Bio-Rad CFX384 C1000 thermal cycler (Bio-Rad laboratories LTD) with a denaturation step of 95° C. for 15 min then 40 cycles at 95° C. for 15 s, 57° C. (gst) or 60° C. (wsp) for 30 s, and 72° C. for 30 s. Quantification was determined by Bio-Rad CFX manager software by comparing the DNA samples to that of a standard curve generated from serial dilution of plasmid DNA of the appropriate gene. Data in Table 3 are expressed as a reduction in Wolbachia load in comparison to the vehicle control group and normalized by positive control (doxycycline at 5 µM).

TABLE 3 Compound (Conc.) % Wolbachia reduction cf. DMSO % Reduction level normalised to DOX (5 µM)

(500 nM) 89.4 99.8

(500 nM) 87.3 97.4

(500 nM) 88.0 98.2

(500 nM) 83.3 92.9 DOX (500 nM) 80.0 92.9 DOX (5 µM) 100.0 DMSO 0 0 DOX = doxycycline

Larval Brugia Malayi Mouse Model

In a larval Brugia malayi mouse model treatment groups (BALB/c IL4Rα-/-mice, 6-8 week old) received compounds by oral delivery for 7 to 14 days commencing on the day of intraperitoneal infection with Brugia malayi third-stage larvae. At 14 days post-infection, larvae were recovered from the peritoneal cavity, counted, and length measured. Genomic DNA was extracted from individual worms (10/group) and quantification of the Wolbachia surface protein (wBm-wsp) gene copy numbers performed by quantitative PCR.

Table 4 shows Wolbachia reductions in Brugia malayi larval infection mouse model (% compared to median vehicle control) following treatment with Compound X orally. Treatment dosage unit is mg/kg (MK) and duration stated in days (d). Abbreviations: DOX (doxycycline), bid (twice daily), Ms (mesylate). Data in Table 4 are expressed as a reduction in Wolbachia load in comparison to the vehicle control group.

TABLE 4 Drug Dose / duration % Wolbachia reduction* DOX 25MKbid +14d 99.05

99.99 Ms salt) 126MKbid+14d

99.91 (Ms salt) 124MKbid+14d

99.84 (Ms salt) 123MKbid+14d *cf median Vehicle

Adult Brugia Malayi Mouse Model

In an adult Brugia malayi mouse model treatment groups (BALB/c CCR3-/-mice, 6-8 week old) received compounds by oral delivery for 7-28 days beginning at 6-10 weeks post-infection intraperitoneal with Brugia malayi third-stage larvae. Following treatment, at 12 weeks post-infection, adult worms and released microfilariae were recovered from the peritoneal cavity, counted and staged for sex. Genomic DNA was extracted from individual adult worms (10/group) and quantification of the Wolbachia surface protein (wBm-wsp) performed by quantitative PCR.

Table 5A shows Wolbachia reductions in Brugia malayi adult infection mouse model (% compared to median vehicle control) following treatment with Compound X orally. Treatment dosage unit is mg/kg (MK) and duration stated in days (d). Abbreviations: MIN (minocycline), bid (twice daily), Ms (mesylate). Data in Table 5A are expressed as a reduction in Wolbachia load in comparison to the vehicle control group.

TABLE 5A Drug Dose / duration % Wolbachia reduction* MIN 25MKbid +28d 83.6

99.4 (Ms salt) 126MKbid+28d

97.8 (free base) 100MKbid+28d

98.8 (free base) 100MKbid+14d

98.5 (free base) 100MKbid+28d *cf median Vehicle

Table 5B provides a comparison of two stereoisomers in the adult Brugia malayi mouse model above at a range of doses and durations of treatment. Data in Table 5B are expressed as a reduction in Wolbachia load in comparison to the vehicle control group.

Drug Dose / duration % Wolbachia reduction* % Microfilaria (Mf) production reduction* Min 25MK bid +28d treatment +14d wash-out 98.2 100

99.7 100 100MK bid +14d treatment +28d wash-out

99.9 100 150MK bid +07d treatment +35d wash-out

97.8 100 100MK bid +07d treatment +35d wash-out

99.7 100 100MK bid +14d treatment +28d wash-out

99.6 100 150MK bid +7d treatment +35d wash-out

86.8 100 100MK bid +07d treatment +35d wash-out

82.2 91.4 50MK bid +07d treatment +35d wash-out *cf median Vehicle

Adult Onchocerca Ochengi Mouse Model

Viable male Onchocerca ochengi were aseptically isolated from naturally parasitized cattle. Between 10-11 male Onchocerca were surgically implanted into the peritoneal cavity of CB.17(BALB/c) SCID mice under anaesthesia. 3 days post O. ochengi surgical implantation, SCID mice received compounds by oral delivery for 14 days. 38 Days after O. ochengi surgical implantation, mice were necropsied to recover the live worms. Genomic DNA was extracted from individual adult worms (10/group) and quantification of the O. ochengi-specific Wolbachia surface protein (wsp) performed by quantitative PCR. Data in Table 6 is expressed as a reduction in Wolbachia load in comparison to the vehicle control group.

Drug Dose / duration % Wolbachia Reduction* DOX 25MK bid +28d 98.7

96.2 100MK bid +14d *cf median Vehicle

All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law).

All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise paragraphed. No language in the specification should be construed as indicating any non-paragraphed element as essential to the practice of the invention.

The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability, and/or enforceability of such patent documents.

This invention includes all modifications and equivalents of the subject matter recited in the paragraphs appended hereto as permitted by applicable law. 

1. A compound of Formula I:

or a salt or solvate thereof, wherein, Q is a group selected from an C₃₋₁₁cycloalkyl optionally substituted by one or more R^(b), 3-15 membered heterocycloalkyl optionally substituted by one or more R^(b), C₆-₁₁ aryl group optionally substituted with by one or more R^(b), 5-15 membered heteroaryl optionally substituted by one or more R^(b). R⁶ is selected from hydrogen and C₁₋₆ alkyl; R⁷ and R⁷′ are independently selected from hydrogen, C₃₋₆ cycloalkyl, C₁₋₆ alkyl, where said C₃₋₆ cycloalkyl and C₁₋₆ alkyl are optionally substituted by one or more R^(a); or R⁷ and R⁷′ together with the carbon to which they are attached form a 3-7 membered cycloalkyl ring, optionally substituted with one or more R^(a), or R⁷ and R⁷′, together with the carbon to which they are attached form a carbonyl group; or R⁶ and R⁷, together with the atoms to which they are attached form a 3-7 membered heterocyclic ring, optionally substituted with one or more R^(a); n is a number selected from 1, 2 and 3; R² is selected from —CN, —C(═O)R^(d), —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d), —NR^(c)C(═O)R^(d), —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d), —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d) OC(═O)R^(d), —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)R^(d), —S(═O)₂R^(d) —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d), —OS(═O)₂NR^(c)R^(d), —S(═O)₂NR^(c)R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl optionally substituted by one or more R^(e), C₂₋₆alkenyl optionally substituted by one or more R^(e), C₂₋₆alkynyl optionally substituted by one or more R^(e), C₆₋₁₁aryl optionally substituted by one or more R^(e), (C₇₋ ₁₆)alkylaryl optionally substituted by one or more R^(e), C₃₋₁₁cycloalkyl optionally substituted by one or more R^(e), (C₄₋₁₇)cycloalkylalkyl optionally substituted by one or more R^(e), 3-15 membered heterocycloalkyl optionally substituted by one or more R^(e), 4-21 membered alkylheterocycloalkyl optionally substituted by one or more R^(e), 5-15 membered heteroaryl optionally substituted by one or more R^(e), and 6-21 membered alkylheteroaryl optionally substituted by one or more R^(e); each R^(a) is independently selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, wherein said C₃₋₆ cycloalkyl and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl; each R^(b) and R^(e) is independently selected from hydroxyl, =O, halogen, CN, C₁-₆ haloalkyl, C₁₋ ₆ haloalkoxy, C₁₋₆ alkyl, O-C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, —C(═O)R^(d),—C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d), —NR^(c)C(═O)R^(d), —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d), —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d), —OC(═O)R^(d), —OC(═O)NR^(c)R^(d),—OC(═O)OR^(d), —S(═O)₂R^(d), —S(═O)R^(d), —OS(═O)R^(d), —OS(═O)₂R^(d),—OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d), —OS(═O)₂NR^(c)R^(d), and —S(═O)₂NR^(c)R^(d), where said C₃₋₆ cycloalkyl, C₁₋₆ alkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl; each R^(c) is independently selected from hydrogen, hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl; each R^(d) is independently selected from hydrogen, hydroxyl, halogen, CN, C₁-₆ haloalkyl, 3-7 membered heterocycloalkyl, C₃-₆ cycloalkyl, C₁-₆ alkyl, O—C₁—₆ alkyl and C₆-₁₁ aryl, wherein said C₁-₆ alkyl, C₆-₁₁ aryl, 3-7 membered heterocycloalkyl and C₃-₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, amino, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋ ₁₁ aryl, 3-7 membered heterocycloalkyl, C₁₋₆ alkyl and O—C₁—₆ alkyl; or R^(c) and R^(d), when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, NH and S, and wherein said ring is optionally substituted with one or more R^(a); R⁴ and R⁵ are independently selected from hydrogen, hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₁-₆ haloalkoxy, C₁-₆ alkyl, phenyl and cyclopropyl, wherein said C₁-₆ alkyl, phenyl and cyclopropyl are optionally substituted by one or more R^(a); with the provisos that: (i) when Q is phenyl, R^(b) is not such that Q is a 3,4-di-O-C₁₋₆ alkyl phenyl, a 3,5-di-O-C₁₋₆ alkyl phenyl or a 3,4,5-tri-O-C₁₋₆ alkyl phenyl; and (ii) the compound of Formula (I) is not N-(4-fluorobenzyl)-2-(piperidinyl-1-yl)pyrido[2,3-d]pyrimidin-4-amine. 2-4. (canceled)
 5. The compound according to claim 1, or a salt or solvate thereof, wherein Q is a group selected from a C₆₋₁₁ aryl group optionally substituted with by 1-11 R^(b) and a 5-15 membered heteroaryl optionally substituted by 1-15 R^(b).
 6. The compound according to claim 1, or a salt or solvate thereof, wherein Q is selected from a phenyl or pyridyl group optionally substituted with 1-5 R^(b).
 7. The compound according to claim 1, or a salt or solvate thereof, wherein Q is a group of Formula III:

wherein X⁴ is selected from CH and N; m is selected from 0, 1 and 2; and R^(b) is as previously defined.
 8. The compound according to claim 1, or a salt or solvate thereof, wherein Q is a group of Formula IIIa:

wherein X⁴ is selected from CH and N; and R^(b) is as previously defined.
 9. (canceled)
 10. The compound according to claim 1, or a salt or solvate thereof, wherein each R^(b) is independently selected from fluoro, chloro, and CF₃.
 11. The compound according to claim 1, wherein R⁶, R⁷ and R^(7′) are each hydrogen.
 12. The compound according to claim 1, or a salt or solvate thereof, wherein n is
 1. 13. (canceled)
 14. (canceled)
 15. The compound according to claim 1, or a salt or solvate thereof, wherein R² is selected from

and

each of which may optionally be substituted with one or more R ^(e).
 16. (canceled)
 17. (canceled)
 18. The compound according to claim 1, or a salt or solvate thereof, wherein each R^(e) is independently selected from fluoro, chloro, CN, CF₃, OCF₃, and methyl.
 19. (canceled)
 20. (canceled)
 21. The compound according to claim 1, or a salt or solvate thereof, which is a sub-Formula Ia:

wherein, R⁶ is selected from hydrogen and C₁₋₆ alkyl; R⁷ is selected from hydrogen, =O, C₃₋₆ cycloalkyl, C₁₋₆ alkyl, where said C₃₋₆ cycloalkyl, C₁₋₆ alkyl are optionally substituted by one or more R^(a); or R⁶ and R⁷, together with the atoms to which they are attached form a 3-7 membered heterocyclic ring, optionally substituted with one or more R^(a); X⁴ is selected from CH and N; R² is selected from —CN, —C(═O)R^(d), —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d)—NR^(c)C(═O)R^(d), —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d), —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d) OC(═O)R^(d), —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)R^(d), —S(═O)₂R^(d), —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d), —OS(═O)₂NR^(c)R^(d), —S(═O)₂NR^(c)R^(d), C₁₋₁₀ haloalkyl, C₁₋₁₀alkyl optionally substituted by 1-13 R^(e), C₂₋₆alkenyl optionally substituted by 1-11 R^(e), C₂₋₆alkynyl optionally substituted by 1-9 R^(e), C₆₋₁₁aryl optionally substituted by 1-11 R^(e), (C₇₋₁₆)alkylaryl optionally substituted by 1-9 R^(e), C₃₋₁₁cycloalkyl optionally substituted by 1-21 R^(e), (C₄₋₁₇)cycloalkylalkyl optionally substituted by 1-32 R^(e), 3-15 membered heterocycloalkyl optionally substituted by 1-28 R^(e), 4-21 membered alkylheterocycloalkyl optionally substituted by 1-40 R^(e), 5-15 membered heteroaryl optionally substituted by 1-15 R^(e), and 6-21 membered alkylheteroaryl optionally substituted by 1-27 R^(e); each R^(a) is independently selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, wherein said C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl; each R^(b) and R^(e) is independently selected from hydroxyl, =O, halogen, CN, C₁₋₆ haloalkyl, C₁₋ ₆haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆ alkyl, O-C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 3-7 membered heterocycloalkyl, C(═O)R^(d), —C(═O)OR^(d), —C(═O)NR^(c)R^(d), —C(O)C(═O)R^(d), —NR^(c)R^(d), —NR^(c)C(═O)R^(d), —NR^(c)C(═O)OR^(d), —NR^(c)C(═O)NR^(c)R^(d), —NR^(c)S(═O)₂R^(d), —NR^(c)S(═O)₂NR^(c)R^(d), —OR^(d), —SR^(d), —OC(═O)R^(d), —OC(═O)NR^(c)R^(d), —OC(═O)OR^(d), —S(═O)₂R^(d), —S(═O)R^(d), —OS(═O)R^(d), —OS(═O)₂R^(d), —OS(═O)₂OR^(d), —S(═O)NR^(c)R^(d), —OS(═O)₂NR^(c)R^(d), and —S(═O)₂NR^(c)R^(d), where said C₃₋₆ cycloalkyl, C₁₋₆ alkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl; each R^(c) is independently selected from hydrogen, hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl; each R^(d) is independently selected from hydrogen, hydroxyl, halogen, CN, C₁₋₆ haloalkyl, 3-7 membered heterocycloalkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyl and O-C₁₋₆ alkyl, C₆₋₁₁ aryl, wherein said C₁₋₆ alkyl, C₆₋₁₁ aryl, 3-7 membered heterocycloalkyl and C₃₋₆ cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₁ aryl, C₁₋₆ alkyl and O-C₁₋₆ alkyl; or R^(c) and R^(d), when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally substituted with one or more R^(a); and R⁴ and R⁵ are independently selected from hydrogen, hydroxyl, halogen, CN, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, and C₁₋₆ alkyl.
 22. The compound according to claim 21, or a salt or solvate thereof, wherein R⁴ and R⁵ are hydrogen.
 23. The compound according to claim 21, or a salt or solvate thereof, wherein each R^(b) is independently selected from fluoro, chloro, and CF₃.
 24. The compound according to claim 21, wherein R⁶ and R⁷ are both hydrogen.
 25. (canceled)
 26. The compound according to claim 21, or a salt or solvate thereof, wherein R² is selected from

and

each of which may optionally be substituted with one or more R ^(e).
 27. The compound according to claim 21, or a salt or solvate thereof, wherein each R^(e) is independently selected from fluoro, chloro, CN, CF₃, OCF₃, and methyl.
 28. (canceled)
 29. (canceled)
 30. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
 31. (canceled)
 32. A combination comprising a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, with one or more additional therapeutic agents.
 33. A method of treating or preventing a filarial worm infection in a subject, said method comprising administering to a subject a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof .
 34. A method of treating or preventing a disease or condition mediated by a filarial worm infection, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof .
 35. (canceled)
 36. (canceled) 